Cause (2/5).....

Keratin Filaments

Keratins 5 and 14 combine to form intermediate filaments in basal keratinocytes. Keratins contain a central alpha-helical rod with several nonhelical interruptions, as well as nonhelical carboxyterminal and aminoterminal regions. The regions of highest conservation between the keratins are located on the ends of the keratin rod in the helix boundary motifs. Keratin intermediate filaments insert upon electron-dense structures termed hemidesmosomes.

Cause (1/5)....

Basement Membrane Zone (BMZ)

Many stratified squamous epithelial tissues, such as the skin and oral mucosa, contain a complex Basement Membrane Zone (BMZ). The BMZ is composed of many specialized components which combine to form anchoring complexes.

 At the superior aspect of the BMZ, keratin-containing intermediate filaments of the basal cell cytoskeleton insert on basal cell plasma membrane condensations termed ‘hemidesmosomes’. Anchoring filaments extend from the basal cell plasma membrane into the extracellular environment and span the lamina lucida, connecting hemidesmosomes with the lamina densa.

At the most inferior aspect of the BMZ, type VII collagen-containing anchoring fibrils extend from the lamina densa into the papillary dermis connecting the lamina densa to anchoring plaques, trapping interstitial collagen fibrils. Thus, the cutaneous BMZ connects the extensive basal cell cytoskeletal network with the abundant network of interstitial collagen fibrils in the dermis.

Type/Epidermolysis Bullosa Acquisita (EBA)

Epidermolysis Bullosa Acquisita (EBA)

Epidermolysis Bullosa Acquisita (EBA) is another rare type of Epidermolysis Bullosa, which isn't inherited. Blistering associated with this condition occurs as the result of the immune system mistakenly attacking healthy tissue. It is similar to a condition called ‘bullous pemphigoid’, which also is related to an immune system disorder. EBA has been associated with Crohn's disease, an inflammatory bowel disease.

Type/Dystrophic Epidermolysis Bullosa (DEB)

Dystrophic Epidermolysis Bullosa (DEB)

Dystrophic Epidermolysis Bullosa (DEB)~ whose subtypes range from mild to severe, generally becomes apparent at birth or during early childhood. In Dystrophic Epidermolysis Bullosa (DEB), the mutation is involved in the production of a type of collagen, a strong protein in the fibers that hold the deepest, toughest layer of your skin together. As a result, the fibers are either missing or non-functional. DEB can be either dominant or recessive.

This is a group of diseases caused by defects of anchoring fibrils. Blisters heal followed by dystrophic scarring. Formation of milia (1- to 4-mm white papules) results as a consequence of damage to hair follicles.

Dominantly inherited dystrophic epidermolysis bullosa

The onset of disease usually is at birth or during infancy, with generalized blistering as a common presentation. With increasing age, an evolution to localized blistering is present. A common variant described by Cockayne-Touraine has an acral distribution and minimal oral or tooth involvement. Another variant described by Pasini features more extensive blistering, scarlike papules on the trunk (termed albopapuloid lesions), and involvement of the oral mucosa and teeth. Dystrophic or absent nails are common in both of these dominantly inherited dystrophic epidermolysis bullosa variants.

Recessively inherited epidermolysis bullosa

This group of diseases ranges from mild to severe in presentation.

A localized form, termed recessively inherited epidermolysis bullosa mitis, often involves acral areas and nails but shows little mucosal involvement. This subtype also demonstrates clinical manifestations similar to the dominantly inherited forms of dystrophic epidermolysis bullosa.

Severe recessively inherited epidermolysis bullosa, as described by Hallopeau-Siemens, usually shows generalized blistering at birth and subsequent extensive dystrophic scarring that is most prominent on the acral surfaces. This can produce pseudosyndactyly (mitten-hand deformity) of the hands and feet. Flexion contractures of the extremities are increasingly common with age. Nails and teeth also are affected. Involvement of internal mucosa can result in esophageal strictures and webs, urethral and anal stenosis, phimosis, and corneal scarring. Malabsorption commonly results in a mixed anemia resulting from a lack of iron absorption, and overall malnutrition may cause failure to thrive. Patients with severe recessively inherited epidermolysis bullosa who survive to childhood are at significant risk of developing aggressive SCC in areas of chronic erosions.

Recessively inherited dystrophic epidermolysis bullosa pseudosyndactyly (mitten-hand deformity) of the hands and feet

Ectodermal dysplasia-skin fragility syndrome is a rare disorder characterized by skin erosions, skin fragility and peeling beginning at birth or infancy that may be accompanied by alopecia, palmoplantar keratoderma, painful fissures, and nail dystrophy. Failure to thrive, cheilitis, hypohidrosis, and pruritus are other potential complications. The underlying molecular defect has been shown to be loss of function of the desmosomal protein plakophillin1. Plakophillin is expressed mainly in suprabasilar keratinocytes and outer root sheath cells. Microscopic findings in this disease usually show intraepidermal acantholysis, located in the areas where plakophillin 1 is normally expressed. The molecular defect involves loss of function mutations in the PKP1 gene coding for plakophillin 1.

Type/Junctional Epidermolysis Bullosa (JEB)

Junctional Epidermolysis Bullosa (JEB)

Junctional Epidermolysis Bullosa (JEB) is usually severe type of the disorder generally becomes apparent at birth. In Junctional Epidermolysis Bullosa (JEB), the mutated genes are involved in the formation of thread-like fibers (hemidesmosomes) whic attach the epidermis to the basement membrane. This gene defect causes tissue separation and blistering in the basement membrane zone (BMZ).

Junctional Epidermolysis Bullosa (JEB) has autosomal recessive inheritance pattern in which both parents carrying one copy of the diseased gene and passing on the mutated gene, although neither parent may clinically have the disorder (silent mutation).

If both parents carry one faulty gene, there's a 25% chance each of their offspring will inherit two mutated genes — one from each parent — and develop the disorder.

Primary subtypes include a lethal subtype termed Herlitz or junctional epidermolysis bullosa letalis, a nonlethal subtype termed junctional epidermolysis bullosa mitis and a generalized benign type termed generalized atrophic benign epidermolysis bullosa.

Lethal junctional epidermolysis bullosa

The Herlitz or letalis form of junctional epidermolysis bullosa is characterized by generalized blistering at birth and arises from an absence or a severe defect in expression of the anchoring filament glycoprotein laminin 5. Patients with lethal forms of junctional epidermolysis bullosa show characteristic periorificial erosions around the mouth, eyes and nares, often accompanied by significant hypertrophic granulation tissue. Multisystemic involvement of the corneal, conjunctival, tracheobronchial, oral, pharyngeal, esophageal, rectal, and genitourinary mucosae is present. Internal complications of the disease include a hoarse cry, cough, and other respiratory difficulties. Patients with Herlitz junctional epidermolysis bullosa are at increased risk for death from sepsis or other complications secondary to the profound epithelial disadhesion and usually they do not survive past infancy.

 Junctional epidermolysis bullosa, Herlitz subtype.

This severe disease is characterized by generalized intralamina lucida blistering at birth, significant internal involvement, and a poor prognosis.

 Nonlethal junctional epidermolysis bullosa

Patients with junctional epidermolysis bullosa manifesting generalized blistering who survive infancy and clinically improve with age have junctional epidermolysis bullosa mitis. Usually, these patients do not present with the same type of hoarse cry or other significant respiratory symptoms as do patients with the Herlitz form. Instead, scalp, nail, and tooth abnormalities increasingly may become apparent. Periorificial erosions and hypertrophic granulation tissue can be present. Mucous membranes often are affected by erosions, resulting in strictures. Some patients with junctional epidermolysis bullosa mitis can present with blistering localized to the intertriginous regions.

Generalized atrophic benign epidermolysis bullosa

This is a relatively mild subtype characterized by generalized cutaneous blistering and presenting at birth. Blistering activity is worsened by increased ambient temperature, and blisters heal with a distinctive atrophic appearance. Extracutaneous involvement is rare, with the exception of teeth. Hypoplastic enamel formation results in significant tooth decay. Nail dystrophies and alopecia are other common clinical manifestations. Individuals with generalized atrophic benign epidermolysis bullosa have the potential to bear children and have a typical life expectancy. It should be noted that generalized atrophic benign epidermolysis bullosa is lumped together with nonlethal junctional epidermolysis bullosa in the newest epidermolysis bullosa classification consensus; however, it is clear that these 2 diseases are quite distinct clinically.

Type/ Epidermolysis Bullosa Simplex (EBS)

Before we move into more details of the genetic of each type & sub-type of Epidermolysis Bullosa (EB) let’s take a brief idea about each type.

 Epidermolysis Bullosa Simplex (EBS)

Epidermolysis Bullosa Simplex (EBS) is the most common and generally mildest form usually begins at birth or during early infancy. EBS is a collection of keratin disorders characterized by intraepidermal blistering with relatively mild internal involvement. Lesions typically heal without scarring. In EBS, mainly the palms of hands and soles of feet are affected. In EBS, the mutated genes are those involved in the production of keratin, a fibrous protein in the top layer of skin. The condition causes the skin to split in the epidermis, which produces blisters, usually scar formation.

Epidermolysis Bullosa Simplex (EBS) is inherited as autosomal dominant pattern. As we discussed earlier for EBS one single mutated gene from any of the parents is enough to develop the symptoms. However, if the parental condition is mild, there is a chance that EBS may not be diagnosed.

Occasionally, EBS may be the first in one’s family to be affected. In these cases, the mutation will have occurred in the womb before the child was born ~ neither of the parents carries the mutation and the child has a new mutation.

After that if EBS first generation go onto have children, they will have a 50% chance of developing Epidermolysis Bullosa Simplex (EBS).

The more severe Epidermolysis Bullosa Simplex (EBS) subtypes include Koebner, Dowling-Meara, and Weber-Cockayne forms.

Mild Epidermolysis Bullosa Simplex

Weber-Cockayne subtype is the most common form of Epidermolysis Bullosa Simplex (EBS). Blisters usually are precipitated by a clearly identified traumatic event. They can be mild to severe and most frequently occur on the palms and soles. ‘Hyperhidrosis’ can accompany this disorder.

Epidermolysis Bullosa Simplex, Weber-Cockayne subtype.

This mild bullous disease is characterized by localized blistering at sites of trauma such as the feet.

Severe Epidermolysis Bullosa Simplex

Usually, a generalized onset of blisters occurs at or shortly after birth. Hands, feet, and extremities are the most common sites of involvement. Palmoplantar hyperkeratosis and erosions are common, especially in Koebner epidermolysis bullosa simplex.

Dowling-Meara epidermolysis bullosa simplex involves more oral mucosa and manifests with grouped herpetiform blisters (hence the term epidermolysis bullosa simplex herpetiformis).

Epidermolysis Bullosa Simplex, Koebner subtype.

Palmoplantar blistering and hyperkeratosis are noted.

Epidermolysis Bullosa Simplex, Koebner subtype.

Close-up image shows hyperkeratotic papules and plaques on the palm.

Inheritance....

How is EB Inherited?

All the genes of a human body come in pairs. We receive one half from our mother and the other half from the father. Genetic disorder such as Epidermolysis Bullosa (EB) is passed to a child from the mother and/or father's chromosomes. All of the genes that cause EB are autosomal i.e. the genes are not carried on the sex-determining (X and Y) chromosomes. Chromosomes are two sets of instruction manuals that contain information on how to make everything in our body. One instruction manual is from our mother and the other is from our father. Genes on chromosomes are like pages or sections of the instruction manual that focus on a specific part of the body, like eye color.

 In individuals with EB, some of the pages (genes) of one or both instruction manuals (chromosomes) are missing or incorrect. These pages should contain the instructions to make the proteins that hold the skin together. Faulty instructions lead to missing or abnormal proteins and the skin is not as strong as it should be. One or two sets of bad instructions produce different forms of EB.

Autosomal Dominant Inheritance

Most forms of EB Simplex and Dominant Dystrophic EB are autosomal dominant - only one mutated gene is enough to develop the disease. The mutated gene is able to disrupt the function of the normal gene. The parent from whom the sufferer inherited the mutated gene also has the symptoms of the conditions.

A person with a dominant form of EB has a 50% chance in each pregnancy of passing the disease on to their child.

A person may have a dominant form of EB and not have an affected parent. In these cases, a new mutation in the egg or sperm of one parent occurred.

Autosomal Recessive Inheritance

All forms of Junctional EB and Recessive Dystrophic EB are autosomal recessive - two abnormal genes are needed to produce disease.

A carrier has one copy of mutated gene for the disease and is completely healthy. If a carrier has a child with another carrier for the same disease, their child may be affected. When two carriers for a disease produce a child, there is a:

• 25% chance the child will have the disease
• 50% chance the child will be a carrier
• 25% chance the child will have completely normal genes.

This information is most useful to parents who have had one child with a recessive form of EB in determining their risk of having another affected child in the future.

Symptoms.....

The primary indication of Epidermolysis Bullosa is the eruption of fluid-filled blisters (Bullae) on the skin, most commonly on the hands and feet in response to friction. Blisters of Epidermolysis Bullosa (EB) typically develop in various areas, depending on the type. In mild cases, blisters heal without scarring.

Signs and symptoms of Epidermolysis Bullosa (EB) include:

ü  Blistering of skin — how widespread and severe depends on the type

ü  Deformity/loss of fingernails and toenails

ü  Internal blistering, including on the throat, esophagus, upper airway, stomach, intestines and urinary tract

ü  Skin thickening on palms and soles of the feet (hyperkeratosis)

ü  Scalp blistering, scarring and hair loss (scarring alopecia)

ü  Thin-appearing skin (atrophic scarring)

ü  Tiny white skin bumps or pimples (milia)

ü  Dental abnormalities, such as tooth decay from poorly formed tooth enamel

ü  Excessive sweating

ü  Difficulty swallowing (dysphagia)

EB skin is never able to ever heal properly with normal strength: chronic open wounds and extensive scarring develop with attendant pain. Each time EB skin is damaged, the damage is irreversible and disfigurement and disability accrue over a lifetime.

The chronic wounds of EB can result in decreased mobility owing to pain and the extensive scar tissue that forms. Scarring in turn results in constriction of the mouth or throat or 'mitten' deformities of the hands and feet: for example benefits of surgery to release fingers are of limited duration as scar tissue starts to form again immediately.

For some types of EB, the internal mucosa is also affected: nutrition can be compromised, resulting in osteoporosis and general failure to thrive—quite young children can depend on gastrostomies or require highly specialised diets.

Mortality...

Infancy is an especially difficult time for Epidermolysis Bullosa (EB) patients. Generalized blistering caused by any subtype may be complicated by infection, sepsis, and death. Severe forms of Epidermolysis Bullosa (EB) increase the mortality risk during infancy. Patients with the Herlitz or letalis form of Junctional Epidermolysis Bullosa [JEB] have the highest risk during infancy with an estimated mortality rate of 87% during the first year of life. The patients with Epidermolysis Bullosa (EB) who survive childhood, the most common cause of death for them is metastatic squamous cell carcinoma (SCC):

Recessively inherited dystrophic Epidermolysis Bullosa (EB), squamous cell carcinoma (SCC)

This skin cancer occurs specifically in patients with recessively inherited Epidermolysis Bullosa (EB) who most commonly are aged 15-35 years. In contrast, dominantly inherited Epidermolysis Bullosa Simplex [EBS] and Dystrophic Epidermolysis Bullosa [DEB] and milder forms of Junctional Epidermolysis Bullosa [JEB] may not affect a patient's life expectancy adversely.

One study reported that from 1979-2002, the overall age-adjusted annual mortality annual mortality rate from bullous skin diseases 0.103 death per 100,000 population (2000 US standard population).

Frequency...

United States

Assuming that mild cases of Epidermolysis Bullosa simplex are reported only 10% of the time; the affected population in the United States is approximately 12,500 persons. According to a National Epidermolysis Bullosa Registry report, 50 Epidermolysis Bullosa cases occur per 1 million live births. Of these cases, approximately 92% are Epidermolysis Bullosa Simplex [EBS], 5% are Dystrophic Epidermolysis Bullosa [DEB], 1% is Junctional Epidermolysis Bullosa [JEB], and 2% are unclassified. Patients with Hemidesmosomal Epidermolysis Bullosa probably constitute much less than 1% of total Epidermolysis Bullosa cases.

International

As per the National Epidermolysis Bullosa Registry, the number of Epidermolysis Bullosa cases in Norway is 54 cases per million live births, in Japan 7.8 cases per million live births and in Croatia is 9.6 cases per million live births.

Pathophysiology

Epidermolysis Bullosa (EB) is classified into 3 major categories:

1.   Epidermolysis Bullosa Simplex (EBS): intraepidermal skin separation

2.   Junctional Epidermolysis Bullosa (JEB): skin separation in lamina lucida or central BMZ

3. Dystrophic Epidermolysis Bullosa (DEB): sublamina densa BMZ separation

These types differ not only phenotypically and genotypically but more importantly by the site of ultrastructural disruption or cleavage.

EB Simplex (EBS) occurs in the outer layer of the skin- further subdivided based on whether blister arise within the basal (i. e. lowermost) or suprabasal (i.e. upper) layer of the ‘Epidermis’.

Junctional EB (JEB) and Dystrophic EB ((DEB) patients develop their blisters within the lamina lucida and sub-lamina densa of the skin basement membrane zone (BMZ) (“Dermoepidermal Junction”) respectively.

Researchers have proposed a new category termed ‘Hemidesmosomal Epidermolysis Bullosa (HEB)’ which produces blistering at the hemidesmosomal level in the most superior aspect of the BMZ.

The Structure......

The Structure of Skin

Before having a better understanding of the causes and symptoms of the Epidermolysis Bullosa (EB) let’s take a look on the structure of the skin.

Human skin is made up of 3 layers:

The Epidermis : The outer layer of the skin.

The Dermis     : The middle layer of skin

The Subcutis   : the deepest layer of skin, mainly made up of fat

The ‘Epidermis’ and ‘Dermis’ meet at a point which is known as ‘Basement Membrane Zone’ (BMZ). This contains specialized proteins like ‘Laminin-332’ ~ acts as a kind of cellular glue ~ which keep the two layers stuck securely together.

Mutation of genes can cause one or more of the proteins in the BMZ to not work properly. This means that trauma of friction to an area of skin could result in the ‘epidermis’ and ‘dermis’ becoming unstuck. If the two layers become separated, a space is created which is then filled with fluid to form a blister.

The Name......

What does the name mean?

The skin is made up of a number of different layers. The outer is called the ‘Epidermis’ and the inner layers are known as ‘Dermis’.

‘Bullosa’ is simply the name for a ‘blister’ and “lysis” means ‘breakdown’.

Hence, ‘Epidermolysis Bullosa’ means the breakdown and blistering of the epidermis.

What is Epidermolysis Bullosa (EB)?

Epidermolysis Bullosa (EB) is a group of blistering skin condition. The shin is so fragile in people with Epidermolysis Bullosa (EB) that even minor rubbing may cause blistering—the person with Epidermolysis Bullosa may not be aware of rubbing or injuring the skin even though blisters develop. In severe EB, blisters are not confined to the outer layer of the skin. They may develop inside the body in such places as the linings of the mouth, esophagus, stomach, intestines, upper airway, bladder and genital.

Epidermolysis Bullosa (EB) encompasses over 30 phenotypically or genotypically distinct entities which share as a common feature mechanical fragility of epithelial lined or surfaced tissues, most notably the ‘skin’. A characteristic feature of all types of EB is the presence of recurrent blistering or erosion, the result of even minor traction to these tissues.

Sufferers of Epidermolysis Bullosa (EB) have compared to sores to 3^rd degree burns.

Butterflies.....................

Skin is a pretty amazing organ. It’s gone through a continuous regeneration procedure where new skin cells (keratinocyte) are born and replace the dead cells that slough off. Before the dead skin cells peels off, they actually serve as the barrier which protects the younger skin and internal organs beneath from exposure to the elements, radiation from the sun and infection from bacteria.

Human skin also has a defense system which goes to work when its integrity gets compromised by injuries from friction or heat. We can see this system in action every time a blister forms on our skin.

When skin is irritated by friction or exposure to high temperatures, the layers can loosen. When this occurs, the empty pocket between the two layers~ ‘epidermis’ & ‘dermis’ [‘Epidermis’ is the outer layer while ‘Dermis’ is the underlying layer] ~ is filled with a fluid called ‘serum’. This serum serves as a cushion that allows the immature, tender skin beneath to heal, a process called re-epithelialization. When it is done, the injured outside layer deadens and falls off.

‘Blister’ is a normal and beneficial reaction to damaged skin. For most of us, they pose little more than a nuisance. But for people who suffer from a condition called Epidermolysis Bullosa (EB), the blisters can be life-threatening.

Epidermolysis Bullosa (EB) is a inherited disorder where mutations on 10 genes lead to a heightened blister response in the sufferer's skin. People who suffers with EB have fragile skin; mild heat and friction can create injuries and cause blisters. While blisters can be painful, consistent and prolonged blistering can also pose a risk to a person's health, as it increases the likelihood that a blister will become infected. [NIAMS]

‘Butterfly children’ is a term often used to describe younger patients—because, the skin is said to be as fragile as a butterfly’s wing. The severe pain hardly allows patients with Epidermolysis Bullosa (EB)  to live a normal life. It is even difficult for the patients to walk because the stress on the soles of the feet causes stabbing pain.

Source: www.howstuffworks.com