Junctional EB

Recurring blistering that often results from friction or minor trauma. Blisters tend to rupture leaving erosions, which can become extensive. Areas of ulcerated skin may be present at birth, most commonly on the lower limbs or dorsa of the feet and ankles. Blisters and ulcers may heal with atrophic scarring and variable hypo- or hyperpigmentation.  Blistering may improve with age. 

Blisters can appear in mucosal surfaces such as the mouth and nose. 

May experience blisters in the eyes or on the conjunctiva, leading to irritation, dryness, scarring and potential visual impairments. 

Scalp blistering may cause patchy or permanent hair loss starting in childhood.

Enamel defects that lead to a higher risk of dental problems. 

Thickened, absent, or misshapen nails. 

Most commonly presents in older individuals with urethral stricture disease.

Development of aggressive cutaneous squamous cell carcinoma (SCC) can occur in adulthood.

Blisters may or may not be present at birth. In the early weeks of life, blisters may be few and tend to occur on the buttocks, elbows, and around the nails. By a few weeks to months of age, wounds may become chronic with friable granulation tissue, commonly affecting the face, ears, and distal digits. Persistent large gluteal wounds are common. Blisters also often rupture, leaving erosions that can become extensive.  

Areas of ulcerated skin may be present from birth, and are most commonly found on the lower limbs, feet, and ankles. Blisters and ulcers can heal with atrophic scarring, leading to hypo- or hyperpigmentation.  

Ocular involvement with corneal blistering and erosions. Pannus formation, scarring and symblepharon may follow episodes of blistering.  

Blistering, erosions, granulation tissue, and scarring commonly affect the laryngeal and upper airway mucosa. This can cause hoarseness, stridor, and difficulty breathing. 

Progressive airway narrowing may lead to life-threatening obstruction, sometimes requiring interventions like tracheostomy. Recurrent infections, aspiration, and respiratory failure are also common due to compromised mucosal integrity. 

Infants usually develop profound failure to thrive despite adequate nutritional intake. Potential life-threatening internal issues, including respiratory complications, and organ involvement, often lead to sepsis or other life-threatening infections. 

Noted Clinical Symptoms 

• Full thickness skin loss over extensive areas of the head, trunk and limbs at birth.  
• Subsequent severe skin fragility.  
• Skin loss can cause deformity of structures such as the ears and nose. Severe phenotypes can present with rudimentary ears.  
• Nail dystrophy and loss.  
• Pyloric atresia is usually evident within the first days-week of life.  
• May have atresia at other gastrointestinal sites e.g. duodenal or anal.  
• Usually lethal within the first few weeks of life despite surgical correction of pyloric atresia.  
• Milder, non-lethal forms have less severe skin and nail involvement but with frequent genitourinary tract involvement. 

Genetics

• Biallelic loss-of-function, splice site or missense pathogenic variants in ITGA6 result in a severe and rapidly lethal phenotype. 
• Biallelic loss-of-function or splice site pathogenic variants in ITGB4 that result in loss of 4 integrin result in a severe and rapidly lethal phenotype. 
• Biallelic loss-of-function, missense, splice site or in-frame deletion mutations in ITGB4 which result in reduced 4 integrin expression result in a milder form of JEB with pyloric atresia. 
• Biallelic mutations in ITGB4 may result in JEB without pyloric atresia.  

Noted Clinical Symptoms 

• Limited cutaneous fragility and blistering, often only acral.  
• Variable nail dystrophy and mucosal involvement.  
• Variable dental enamel defects.  
• Normal hair.  

Genetics

• Autosomal recessive inheritance.  
• Homozygous or compound heterozygous pathogenic variants in COL17A1, LAMA3, LAMB3, LAMC2, ITGB4, ITGA3. 

Noted Clinical Symptoms 

• Onset of blistering from birth in flexural sites.  
• Atrophic scarring.  
• Dental enamel abnormalities.  
• Variable nail loss.

 
Genetics

• Pathogenic variants associated with residual expression of laminin 332.77  

Noted Clinical Symptoms 

• Onset of skin fragility in childhood often starting acrally.  
• Progressive fragility with age.  
• Healing with skin atrophy and loss of dermatoglyphs.  
• Scarring leading to flexion contractures of the fingers and reduction of mouth opening may occur with age.  
• Variable dental enamel and nail involvement.  

Genetics

• Autosomal recessive inheritance.  
• Biallelic pathogenic variants in COL17A1, specifically the missense variant c.3908G>A, p.R1303Q, cause this phenotype. 

Syn. Shabbir syndrome.  

Noted Clinical Symptoms 

• Onset of skin fragility from birth with blistered areas leaving erosions and granulation tissue (much more than JEB severe).  
• Predilection for the face and neck.  
• Nail dystrophy and loss with granulation tissue of the nail beds.  
• Conjunctival and eyelid granulation tissue leading to symblepharon, scarring and impaired vision.  
• Laryngeal granulation tissue leading to respiratory obstruction which can be lethal.  
• Profound Anaemia is a major feature due to bleeding from over granulating wounds. 

Genetics

• Autosomal recessive inheritance.  
• Most cases in Punjabi Muslim individuals with a homozygous founder single nucleotide insertion mutation in exon 39 of LAMA3 which is specific to the LAMA3A isoform. 
• Compound heterozygosity for mutations in LAMA3A and LAMA3 result in a similar JEB-LOC phenotype. 

syn. ILNEB, interstitial lung disease, nephrotic syndrome and epidermolysis bullosa

Noted Clinical Symptoms

• Variable cutaneous features with absence or presence of skin fragility from infancy.  
• Nails may be dystrophic and hair may be sparse.  
• Interstitial lung disease and nephrotic syndrome predominate the phenotype, and can be diagnosed soon after birth.  
• Death in infancy or early childhood is the norm.  

Genetics

• Most reported cases result from homozygous loss-of-function pathogenic variants in ITGA3. 
• Missense ITGA3 mutations reported in milder cases surviving to later childhood.