EB in Depth

Noted Clinical Symptoms  

• Skin blistering starts at birth and is generalized, of intermediate severity.  

• Mottled or reticulate pigmentation develops gradually  

• Focal keratoses of the palms and soles, and dystrophic, thickened nails occur over time.  

Genetics

• Autosomal dominant inheritance.  

• The keratin 5 monoallelic pathogenic variant c.74C>T, p.P25L typically causes this phenotype,13 but cases with other variants in KRT5, KRT14 or EXPH5 have been reported.  

Noted Clinical Symptoms  

• Multiple vesicles are present from birth onwards and acquire over time a typical circinate migratory pattern on an erythematous background; post-inflammatory hyperpigmentation develops gradually and may have a mottled pattern.  

• Nails may be dystrophic.  

Genetics

• Autosomal dominant inheritance.  

• Monoallelic pathogenic variants in KRT5 which affect the variable 2 domain and result in frameshift and elongated keratin 5 polypeptide cause this phenotype. 

Noted Clinical Symptoms  

• Extensive skin defects on the extremities are present at birth and heal with hypo- and hyperpigmentation and skin atrophy, initially resembling burn-like scars. Skin blistering diminishes in adulthood, but fragility persists, with erosions occurring after minimal mechanical trauma.  

• Diffuse or focal plantar keratoderma.  

• Nail thickening and onychogryphosis. 

• Diffuse alopecia has been reported in some adult patients.  

• Dilated cardiomyopathy has been reported in young adulthood. Laboratory screening (pro-BNP, creatine kinase, creatine kinase MB) should be started as early as the age of 2 years, with yearly follow-ups. If pathologic values are found, cardiologic examination, ECG and cardiac ultrasound should be performed.   

Genetics

• Autosomal dominant inheritance.  

• Monoallelic pathogenic variants in the translation initiation codon of KLHL24, coding for the kelch-like member 24 cause this disorder.  

• High rate (50%) of de novo mutations. 

Noted Clinical Symptoms  

• Skin blistering starts at birth and is generalized and severe in most cases. No improvement of cutaneous fragility is expected with age. Healing of lesions leads to post-inflammatory hyperpigmentation.  

• Absence of keratin 5 leads to widespread blisters and erosions and early lethality. 

Genetics

• Autosomal recessive inheritance.  

• Biallelic nonsense, missense or frameshift KRT14 pathogenic variants. 

• Biallelic loss-of-function or missense KRT5 pathogenic variants.  

Noted Clinical Symptoms  

• Skin blistering starts at birth or in childhood and is mostly localized to acral extremities.  

• Plantar keratoderma.  

• Nail dystrophy.  

Genetics

• Autosomal recessive inheritance.  

• Biallelic loss-of-function pathogenic variants in DST lead to absence of BP230 and cause this subtype. 

Noted Clinical Symptoms  

• Generalized skin blistering starts at birth or in infancy. Blistering tendency may diminish with age, while crusts and scabs reflect the fragility of the skin.  

• Mild mottled pigmentary changes may develop. 

Genetics

• Autosomal recessive inheritance.  

• Biallelic loss-of-function pathogenic variants in EXPH5 lead to absence of exophilin 5 and cause this subtype.  

Noted Clinical Symptoms  

• Skin blistering starts at birth, is mainly acral but may be widespread. The autosomal dominant subtype is characterized by a mild course, mainly acral erosions and postlesional violaceous and hypopigmented macules. Only three cases with the autosomal recessive subtype have been published yet, all of intermediate severity. 

• Plantar keratoderma.  

• Dystrophic thickened nails, sometimes onychogryphosis.  

• No muscular dystrophy.  

Genetics

• Autosomal dominant or recessive inheritance.  

• The monoallelic PLEC pathogenic variant, c.5998C>T, p.R2000W causes the autosomal dominant subtype previously known as EBS Ogna. 

• Biallelic pathogenic variants in the exon 1a of the PLEC1a isoform (expressed in skin, but not in muscles), in particular, c.46C>T, p.R16*, cause the autosomal recessive subtype.  

Noted Clinical Symptoms  

• Generalized skin blistering starts at birth and is of intermediate severity. Blistering tendency diminishes with age.  

• Focal plantar keratoderma.  

• Nail dystrophy and loss.  

• Mucosal involvement including oral, ocular and urethral mucosae is common.  

• Dental anomalies.  

• Muscular dystrophy starts at a variable age, ranging from infancy to adulthood. 

• Cardiomyopathy may be associated. 

• Granulation tissue and stenosis of the upper respiratory tract and hoarseness may occur. 

• Muscular dystrophy is usually life-limiting in childhood or early adulthood.  

• Pyloric atresia may be associated in rare cases. 

Genetics

• Autosomal recessive inheritance.  

• Biallelic loss-of-function pathogenic variants in PLEC coding for plectin cause this phenotype. They result in lack of immunoreactivity for plectin and a plane of cleavage deep within the basal pole of the basal keratinocytes.  

Noted Clinical Symptoms

• Widespread full-thickness congenital absence of skin.  

• Pyloric atresia.  

• Involvement of the oral mucosa.  

• Anemia and growth retardation.  

• Neonatal lethal course.  

Genetics

• Autosomal recessive inheritance.  

• Biallelic loss-of-function pathogenic variants in PLEC cause this phenotype. 

Noted Clinical Symptoms

• Only a few individuals with this subtype have been reported so far in the literature. 

• Skin blistering starts at birth and is widespread primarily in the pretibial area but also scattered on other parts of the body, particularly those exposed to trauma.  

• Facial freckling, poikiloderma and atrophy of the skin, and acrogeria of the backs of the hands on the sun-exposed areas reported in one case. 

• Erosions of the oral mucous membranes.  

• Nail dystrophy.  

• Early-onset alopecia.  

• Nasolacrimal duct stenosis.  

• Oesophageal webbing and strictures.  

• Nephropathy manifesting with proteinuria. The scarcity of reported cases precludes firm screening recommendations, but annual urinalysis and urea and electrolytes should probably be undertaken following diagnosis.  

Genetics

• Autosomal recessive inheritance.  

• Biallelic loss-of-function pathogenic variants in CD151, coding for the CD151 antigen cause this EBS subtype. 

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. 

Noted Clinical Symptoms

• Usually presents initially as localized or intermediate DDEB or RDEB in childhood and early adulthood.  
• Characterized by intensely pruritic, excoriated violaceous papules or linear plaques and scars particularly on the lower legs, thighs and arms which can become more progressive from adolescence through adulthood.  
• Nail dystrophy and milia are common.  
• May co-exist with non-pruriginosa DEB within families.  

Genetics

• Autosomal dominant or autosomal recessive inheritance.  
• Monoallelic or biallelic mutations in COL7A1 similar to those identified in non-pruriginosa DDEB or RDEB without identification of a specific genotype-phenotype correlation for the pruriginosa phenotype.102–104  

syn. bullous dermolysis of the newborn

Noted Clinical Symptoms 

• Skin blistering presents at or shortly after birth, usually on the extremities.  
• Aplasia cutis of the lower limbs may be present.  
• Scarring and milia occur at sites of blistering.  
• Skin fragility improves spontaneously and may resolve completely over the first year or two of life although nail dystrophy, particularly of the toenails, may persist throughout life.  

Genetics

• Autosomal dominant or autosomal recessive.  
• COL7A1 missense mutations, especially glycine substitutions, are most commonly associated but in-frame deletion, premature termination codon and alternative splicing mutations also described. 
• Characteristic intra-epidermal retention of type VII collagen on immunohistochemistry and stellate bodies in dilated rough endoplasmic reticulum on transmission electron microscopy. These changes tend to improve in parallel with phenotypic improvement.  

Noted Clinical Symptoms  

• In the neonatal period and childhood skin blistering is usually generalized and of intermediate severity.  
• From adolescence to early adulthood, a predilection for flexural sites develops, specifically in the axillae, groins, perianal area and natal cleft. In women, there may be marked vulvovaginal and inframammary skin blistering.  
• Mucosal disease with blistering and scarring in the mouth and oesophagus is characteristic.  
• Involvement of the external auditory canal may lead to narrowing or complete occlusion.  
• Nail involvement is common.  

Genetics

• Autosomal recessive inheritance.  
• Usually results from compound heterozygosity for a loss-of-function COL7A1 mutation in combination with a missense mutation; specific glycine and arginine substitutions have been suggested as causative for this specific phenotype. 

Noted Clinical Symptoms 

• Skin fragility usually presents at or shortly after birth but may rarely be of late onset in adulthood.  
• Blistering is limited in extent; it may affect predominantly the hands and feet, but in others may be restricted to the pretibial area.  
• Nail dystrophy and loss are common.  
• Oral and esophageal mucosal involvement are usually mild or absent.  

Genetics

• Autosomal recessive inheritance.  
• Compound heterozygosity for COL7A1 missense, splice site and frameshift mutations described. 

Noted Clinical Symptoms  

• Severe skin and mucosal fragility presenting from birth indistinguishable from severe RDEB.  
• May have a family history of DDEB in family members.  

Genetics

• Compound heterozygosity for a dominant COL7A1 glycine substitution mutation and a recessive mutation on the second allele.