About EB Junctional

EB Junctional

According to the Debra International Website:
Junctional EB
Early studies attempted to link JEB to abnormalities in tissue enzymes. In 1984 for example, Kero, Palotie, and Peltonen identified a few JEB fibroblast cell lines in which collagenase synthesis was elevated. Similarly, in 1984 and 1985, Manabe and colleagues and Matsumoto and colleagues reported that the exposure of human skin explants to JEB blister fluid resulted in the production of intralamina lucida cleavage. As in the case of identical studies in EBS, these findings were later refuted. In 1986, Heagerty and colleagues demonstrated lack of staining of Herlitz JEB skin by a monoclonal antibody (GB3) that was later shown to be directed against the anchoring filament-associated macromolecule, laminin-5, suggesting that this particular protein might be a target for mutation or injury in JEB. Similar findings were reported by Fine, Horiguchi, and Couchman in 1989 using a monoclonal antibody (19-DEJ-1) against a different anchoring filament-associated protein, now named uncein. In 1994, Jonkman and colleagues demonstrated absent staining of bullous pemphigoid antigen-2 (BP- 180; type XVII collagen) in the skin of a patient with the GABEB subtype of JEB.
These immunohistochemical studies set the stage for the search for mutations in the genes encoding for several skin basement membrane proteins, most notably laminin-5 and bullous pemphigoid antigen-2. As early as 1994, Uitto and colleagues demonstrated that a number of patients with Herlitz and non-Herlitz subtypes of JEB had mutations in the genes encoding for any of the three chains of laminin-5. In 1995, Vidal and co-workers demonstrated the presence of mutations in the gene encoding for the a 4 subunit of a 6b 4 integrin, a component of the hemidesmosome, in a patient having JEB in association with congenital pyloric atresia. In 1996, a few patients with GABEB were shown to have mutations in the gene for bullous pemphigoid antigen-2, confirming the immunohistochemical findings by Jonkman in this particular JEB subtype. In 1997, a patient with GABEB was shown to have mitotic gene conversion of one parental mutation in the gene (COL17A1) encoding for bullous pemphigoid antigen-2, resulting in reversion of the phenotype in a mosaic pattern, the first time such a mechanism has been demonstrated in humans.
Junctional EB
What is the cause of Junctional EB?
Through research it is now known that mutations in genes encoding (Laminin 5, alpha 6, beta 4 integrin and collagen XVII) contribute to defects within hemidesmosomes.

Hemidesmosomes are proteins that form the site of attachment between the basal surface of the cells and the basement membrane. The defect within the skin, will allow for the separation of tissue and blister formation whenever there is friction or trauma to an area.

There are three major sub-types of Junctional EB. Herlitz, non-Herlitz and Junctional EB with associated Pyloric Atresia. Though Junctional EB is considered a non-scarring form of EB tightening and thinning of the skin does occur. Secondary infection can cause scarring.

How is Junctional EB Inherited?

JEB is an autosomal recessive condition. This means both parents are healthy carriers. Healthy carriers are non-symptomatic and will never develop the illness. When each parent has a copy of the altered gene, there is a 25% or 1 in 4 chance the child will be affected by Junctional EB. Unfortunately, there is no test to detect carriers for JEB. We are made aware that the parents are carriers after the child is born.

Junctional Herlitz EB:

Junctional Herlitz EB is a very severe form of EB. These infants often die during infancy due to overwhelming infection (sepsis), malnutrition, dehydration, electrolyte imbalance or complications resulting from blistering in the respiratory, gastrointestinal or genitourinary tract.

Some babies develop a hoarse cry and breathing difficulties which indicates internal involvement as well. These infants often fail to gain weight. These are usually symptoms of the severe form of Junctional EB.

Blistering is usually present at birth, however, there have been instances of infants being discharged to home, with a small blister on the finger or lip. After they are home, the blistering becomes more apparent warranting a visit to the physician. Skin blistering and ulcerations can occur spontaneously on the arms, hands, finger tips, back of the head, neck, shoulders, trunk, buttocks, legs and feet and toes (generalized distribution). Nails may be ulcerated or dystrophic. Warmer climates can exacerbate blistering. Blistering is noted on perioral (around the mouth) and mucosal surfaces as well. Oral lesions may affect eating causing weight loss.

Electron microscopic evaluation of the structure of the skin in a patient affected with JEB-H usually shows skin separation in the lamina lucida within the basement membrane zone. Absent or reduced amounts of hemidesmosomes may also be apparent.

Junctional Herlitz EB mutations are present on one of the three chains of Laminin 5.

Junctional non-Herlitz EB:

Generalized blistering and mucosal involvement may be evident at birth or soon after. Blistering may be mild to severe. Erosions on finger and toenails, nail dystrophy or absence of nails may be evident. Erosions and loss of hair (alopecia) upon the scalp may occur. Granulation tissue around mouth and nares may be seen. There may be some scarring and thinning of the skin on affected areas (atrophic scarring). Warmer climates can exacerbate blistering and pain that can also cause seizures, so is good to have access to a list of anti-seizure medication from the eDrugSearch site online. Though laryngeal involvement (hoarse cry) may be experienced in early infancy, respiratory distress is a rare occurrence in this type of Junctional EB.

The infant may suffer complications such as infection, dehydration, electrolyte imbalances, respiratory, gastrointestinal, and/or genitourinary tract involvement. These complications may lead to death.

Electron microscopic evaluation of the structure of skin in a patient affected with JEB-nH shows skin separation at the level of the lamina lucida of the basement membrane zone. Variable appearance of hemidesmosomes may be visualized as well.

JEB-nH mutations usually involve the genes encoding type XVII collagen also called (BP 180 ). Occasionally mutations in laminin 5 are seen.

Junctional EB with Pyloric Atresia:

Some infants are born with Junctional EB and have been observed to have pyloric atresia, in which the opening between the stomach and the intestines fails to form. Surgery is necessary to repair the anomaly.

Generalized blistering, ulcerations of skin and mucous membranes is usually evident at birth. Blistering may be mild to severe. Erosions on finger and toenails, nail dystrophy or absence of nails may be evident. Erosions and loss of hair (alopecia ) upon the scalp and granulation tissue around mouth and nares may occur. There may be some scarring and thinning of the skin on affected areas (atrophic scarring). Warmer climates can exacerbate blistering.

The infant may suffer complications such as infection, dehydration, electrolyte imbalances, respiratory, gastrointestinal, and/or genitourinary tract involvement. These complications may lead to death.

Electron microscopic evaluation of the structure of the skin of a person affected with JEB-PA reveals skin separation at the level of the lamina lucida, small hemidesmosomal plaques and reduced amount of keratin filaments with hemidesmosomes.

Mutations in JEB-PA are within the genes encoding either alpha 6 or its partner beta 4 integrin. These components of the hemidesmosome are found both in skin and the stomach, explaining the failure of formation of the first part of the intestine (the pylorus).

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

Common Manifestations of JEB: 

  • Blisters/erosions
  • Dystrophic nails – The presence of rough, thickened finger or toenails.
  • Atrophic scarring – Depressions in skin as a result of thinning in epidermis or dermis.
  • Granulation tissue is the appearance of very red fleshy tissue, which is capillary formation during tissue healing. (More apparent in the perioral region and the nares.)
  • Scalp abnormalities. Presence of blisters on scalp and/or scarring alopecia (areas of scarring with absence of hair growth).
  • Respiratory tract involvement. May be present in the more severely affected individual.
  • Anemia – A reduced amount of red blood cells and 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. The globin portion of hemoglobin is made up of protein. (This is more common in the severely affected individual.)
  • Growth retardation and malnourishment.
  • Problems in the soft tissue inside the mouth.
  • Enamel hypoplasia – The presence of underdeveloped enamel upon the teeth.
  • Dental caries is the development of cavities in teeth.
  • Gastrointestinal tract involvement (blisters in mouth, esophagus and/or anal margins).
  • Ocular (eye) involvement.

Rare Manifestations of JEB: 

  • Genitourinary tract involvement may include scarring and/or urethral stenosis.
  • Milia – Small skin cysts
  • Pseudosyndactyly – Fusion/ webbing of fingers and/or toes. On rare instances this has been reported in JEB patients.

There is no evidence that people with Junctional EB are at higher risk for developing malignant melanoma. In rare instances squamous cell carcinoma has been reported.

Any suspicious lesions should be evaluated by a determologist.

Junctional: blistering at the lamina lucida level
Herlitz (junctional epidermolysis bullosa letalis) patients heal very slowly. This may be due to a defect of laminin-5 (a protein shown to be intimately involved in keratinocyte adhesion and migration).
Laminin-5 is absent or reduced in the skin and multiple other organs of individuals with the lethal (Herlitz) form, as determined by IF microscopy using a variety of laminin-5 mAbs including K140, GB3, 46. Mutations of the genes coding for all three subunits of laminin-5 have been demonstrated in families with Herlitz JEB The outmoded terms for laminin-5 including epiligrin, kalinin, or nicein are still occcasionally used by some authors. Mutations of the gene coding for the hemidesmosomal component BP180 have been demonstrated in individuals with the less severe generalized atrophic benign form. Interestingly, structural mutations of LAMB3, one of the genes coding for laminin-5, have also been demonstrated in individuals with this disease. Absence of IF staining of mAb 123 which recognizes the anchoring filament component LAD-1, has also been demonstrated in the skin of individuals with this disease, however it is unclear at present if this is due to mutations of the gene coding for this protein or if the absent staininig represents a secondary defect. Mutations of the gene coding for the b4 integrin subunit have been demonstrated in the form of junctional epidermolysis bullosa associated with pyloric atresia. The mAb 19DEJ-1 recognizes an anchoring filament epitope which is absent in both the lethal and nonlethal forms of junctional EB a well as many cases of dystrophic EB, including cases with demonstrated mutations of laminin-5, BP180, b4 integrin or type VII collagen gene mutations. The identity of this 19DEJ-1 antigen, which has been named uncein, remains unclear. It is also unclear whether absence of 19DEJ-1 staining on JEB skin could in some cases represent a primary defect or whether, as in the cases of JEB caused by known mutations the absence of staining represents a secondary event.

According to the Telemedicine Website of Stanford University:

Picture of a patient with severe Junctional-Herlitz (lethalis).
A) Junctional EB- Gravis (Herlitz Disease)
INHERITANCE: Autosomal Recessive
CUTANEOUS FINDINGS:
  • frequently congenital erosions and occasionally deeper skin defects are present
  • generalized blistering occurs with prominent acral involvement
  • onycholysis with repeated nail loss, sometimes permanently
  • lesions heal slowly and frequently with resultant atrophy and occasional mild scarring
  • vegetating lesions are frequent, especially in the perioral region

EXTRACUTANEOUS FINDINGS:

  • nasal, oral, pharyngeal, esophageal, vaginal, and anal mucosa may be involved
  • eyes, pylorus (atresia), small intestine, gall bladder, urethra, and kidney (hydroureteronephrosis) may also be affected
  • teeth are severely dystrophic
  • retarded general growth
  • anemia
  • death commonly occurs within a few weeks, but some patients survive for a few years, although rarely to adolescence

PATHOLOGIC FINDINGS:

  • blistering at the plane of the lamina lucida, variable alteration of hemidesmosomes and defective anchoring filaments
Picture of a patient with mild Junctional, showing non scarring diffuse alopecia.
B) Junctional EB- Generalized Atrophic Benign
INHERITANCE: Autosomal Recessive
CUTANEOUS FINDINGS:
  • generalized blistering tendency, usually from birth
  • erosions may be extensive and slow to heal
  • hair loss is frequent but variable
  • nails are generally involved with dystrophy or eventual loss
  • healing often occurs with atrophy

EXTRACUTANEOUS FINDINGS:

  • nasal, oral, esophageal, vaginal and anal mucosa are frequently involved
  • eyes, larynx, bladder, urethra and kidney are affected less frequently
  • teeth are dystrophic
  • patients achieve normal or near normal stature
  • life span may be normal or decreased

PATHOLOGIC FINDINGS:

  • separation of the dermis from the epidermis at the level of the lamina lucida with variable hemidesmosome alterations

C) Junctional EB- Localized

INHERITANCE: Autosomal Recessive

CUTANEOUS FINDINGS:

  • from birth, blistering is limited to hands, feet and sometimes the pretibial region
  • nails are regularly involved with repeated and sometimes permanent loss

EXTRACUTANEOUS FINDINGS:

  • good growth and development
  • nasal and oral mucosa may be moderately involved
  • teeth are dystrophic

PATHOLOGIC FINDINGS:

  • blistering at the level of the lamina lucida and variable alterations of hemidesmosomes

D) Junctional EB- Cicatricial

INHERITANCE: Autosomal Recessive

CUTANEOUS FINDINGS:

  • blistering is present from birth
  • distribution is generalized and most severe on hands and feet
  • scarring on healing, sometimes development of syndactyly (mitten type) and contractures occur
  • nails are lost early in life
  • alopecia

EXTRACUTANEOUS FINDINGS:

  • there may be stenosis of the nares, oral blistering, dysplastic teeth, esophageal involvement, laryngeal involvement, and anemia
  • occasional renal and ocular involvement
  • lifespan is uncertain, some patients have reached adulthood

PATHOLOGIC FINDINGS:

  • blister formation at the level of the lamina lucida

E) Junctional EB- Inversa

INHERITANCE: Autosomal Recessive

CUTANEOUS FINDINGS:

  • frequently neonatal erosions (sometimes vegetating) and blisters
  • lesions are generalized early but later are concentrated in the inverse sites (axilla, groin)
  • some acral involvement continues
  • lesions heal with mild atrophy, and some heal with a circumscribed appearance similar to the papuloidea lesions of albopapuloidea dystrophic EB
  • nails are generally involved

EXTRACUTANEOUS FINDINGS:

  • corneal erosions may be present
  • mild to moderate oral, anal and esophageal involvement

PATHOLOGIC FINDINGS:

  • blistering at the plane of the lamina lucida

F) Junctional EB- Progressiva (Neurotropica)

INHERITANCE: Autosomal Recessive

CUTANEOUS FINDINGS:

  • manifestations are delayed until age 5 to 8 years at which time nail dystrophy begins
  • later there is blistering of hands and feet, especially of the palms and soles
  • healing is accompanied by variable atrophy that is most striking on the hands, feet, elbows and knees

EXTRACUTANEOUS FINDINGS:

  • oral blisters and loss of lingual papillae are present
  • the may be mild finger contractures
  • hypoacusis is frequently present

PATHOLOGIC FINDINGS:

  • blistering at the plane of the lamina lucida where amorphous material is deposited

According to the Debra U.S. Website:

Junctional EB
What is the cause of Junctional EB?
Through research it is now known that mutations in genes encoding (Laminin 5, alpha 6, beta 4 integrin and collagen XVII) contribute to defects within hemidesmosomes.

Hemidesmosomes are proteins that form the site of attachment between the basal surface of the cells and the basement membrane. The defect within the skin, will allow for the separation of tissue and blister formation whenever there is friction or trauma to an area.

There are three major sub-types of Junctional EB. Herlitz, non-Herlitz and Junctional EB with associated Pyloric Atresia. Though Junctional EB is considered a non-scarring form of EB tightening and thinning of the skin does occur. Secondary infection can cause scarring.

How is Junctional EB Inherited?

JEB is an autosomal recessive condition. This means both parents are healthy carriers. Healthy carriers are non-symptomatic and will never develop the illness. When each parent has a copy of the altered gene, there is a 25% or 1 in 4 chance the child will be affected by Junctional EB. Unfortunately, there is no test to detect carriers for JEB. We are made aware that the parents are carriers after the child is born.

Junctional Herlitz EB:

Junctional Herlitz EB is a very severe form of EB. These infants often die during infancy due to overwhelming infection (sepsis), malnutrition, dehydration, electrolyte imbalance or complications resulting from blistering in the respiratory, gastrointestinal or genitourinary tract.

Some babies develop a hoarse cry and breathing difficulties which indicates internal involvement as well. These infants often fail to gain weight. These are usually symptoms of the severe form of Junctional EB.

Blistering is usually present at birth, however, there have been instances of infants being discharged to home, with a small blister on the finger or lip. After they are home, the blistering becomes more apparent warranting a visit to the physician. Skin blistering and ulcerations can occur spontaneously on the arms, hands, finger tips, back of the head, neck, shoulders, trunk, buttocks, legs and feet and toes (generalized distribution). Nails may be ulcerated or dystrophic. Warmer climates can exacerbate blistering. Blistering is noted on perioral (around the mouth) and mucosal surfaces as well. Oral lesions may affect eating causing weight loss.

Electron microscopic evaluation of the structure of the skin in a patient affected with JEB-H usually shows skin separation in the lamina lucida within the basement membrane zone. Absent or reduced amounts of hemidesmosomes may also be apparent.

Junctional Herlitz EB mutations are present on one of the three chains of Laminin 5.

Junctional non-Herlitz EB:

Generalized blistering and mucosal involvement may be evident at birth or soon after. Blistering may be mild to severe. Erosions on finger and toenails, nail dystrophy or absence of nails may be evident. Erosions and loss of hair (alopecia) upon the scalp may occur. Granulation tissue around mouth and nares may be seen. There may be some scarring and thinning of the skin on affected areas (atrophic scarring). Warmer climates can exacerbate blistering. Though laryngeal involvement (hoarse cry) may be experienced in early infancy, respiratory distress is a rare occurrence in this type of Junctional EB.

The infant may suffer complications such as infection, dehydration, electrolyte imbalances, respiratory, gastrointestinal, and/or genitourinary tract involvement. These complications may lead to death.

Electron microscopic evaluation of the structure of skin in a patient affected with JEB-nH shows skin separation at the level of the lamina lucida of the basement membrane zone. Variable appearance of hemidesmosomes may be visualized as well.

JEB-nH mutations usually involve the genes encoding type XVII collagen also called (BP 180 ). Occasionally mutations in laminin 5 are seen.

Junctional EB with Pyloric Atresia:

Some infants are born with Junctional EB and have been observed to have pyloric atresia, in which the opening between the stomach and the intestines fails to form. Surgery is necessary to repair the anomaly.

Generalized blistering, ulcerations of skin and mucous membranes is usually evident at birth. Blistering may be mild to severe. Erosions on finger and toenails, nail dystrophy or absence of nails may be evident. Erosions and loss of hair (alopecia ) upon the scalp and granulation tissue around mouth and nares may occur. There may be some scarring and thinning of the skin on affected areas (atrophic scarring). Warmer climates can exacerbate blistering.

The infant may suffer complications such as infection, dehydration, electrolyte imbalances, respiratory, gastrointestinal, and/or genitourinary tract involvement. These complications may lead to death.

Electron microscopic evaluation of the structure of the skin of a person affected with JEB-PA reveals skin separation at the level of the lamina lucida, small hemidesmosomal plaques and reduced amount of keratin filaments with hemidesmosomes.

Mutations in JEB-PA are within the genes encoding either alpha 6 or its partner beta 4 integrin. These components of the hemidesmosome are found both in skin and the stomach, explaining the failure of formation of the first part of the intestine (the pylorus).

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

Common Manifestations of JEB: 

  • Blisters/erosions
  • Dystrophic nails – The presence of rough, thickened finger or toenails.
  • Atrophic scarring – Depressions in skin as a result of thinning in epidermis or dermis.
  • Granulation tissue is the appearance of very red fleshy tissue, which is capillary formation during tissue healing. (More apparent in the perioral region and the nares.)
  • Scalp abnormalities. Presence of blisters on scalp and/or scarring alopecia (areas of scarring with absence of hair growth).
  • Respiratory tract involvement. May be present in the more severely affected individual.
  • Anemia – A reduced amount of red blood cells and 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. The globin portion of hemoglobin is made up of protein. (This is more common in the severely affected individual.)
  • Growth retardation and malnourishment.
  • Problems in the soft tissue inside the mouth.
  • Enamel hypoplasia – The presence of underdeveloped enamel upon the teeth.
  • Dental caries is the development of cavities in teeth.
  • Gastrointestinal tract involvement (blisters in mouth, esophagus and/or anal margins).
  • Ocular (eye) involvement.

Rare Manifestations of JEB: 

  • Genitourinary tract involvement may include scarring and/or urethral stenosis.
  • Milia – Small skin cysts
  • Pseudosyndactyly – Fusion/ webbing of fingers and/or toes. On rare instances this has been reported in JEB patients.

There is no evidence that people with Junctional EB are at higher risk for developing malignant melanoma. In rare instances squamous cell carcinoma has been reported.

Any suspicious lesions should be evaluated by a determologist.

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