EB Simplex

Most often seen on hands and feet, especially after friction or heat. 

Small white cysts that can appear in the first weeks of life. 

Thickened, hardened skin on the soles of the feet that can become painful and limit mobility. 

Toenails or fingernails may become unusually thick or misshapen. 

Large, dark, irregular birthmark-like patches that may form where blisters have repeatedly healed. These are benign but may resemble melanoma.

Blisters typically begin in infancy and may lessen with age, sometimes becoming more limited to the hands and feet during adolescence. 

Unlike localized EBS, blistering is not limited to hands and feet and can appear anywhere on the body. 

Thickening of the soles of the feet can develop gradually, become painful, limit mobility, and impact quality of life.

Tiny white bumps (milia) often appear within the first few weeks of life. 

Large, dark, irregular birthmark-like patches that may form where blisters have repeatedly healed. These are benign but may resemble melanoma. 

Nails may appear thick, damaged, or dystrophic, and in some cases, they may become loose or fall off. Nails may grow back, though repeated damage may lead to permanent loss or abnormal regrowth. 

Widespread and severe, including large blisters that may appear spontaneously or from very light friction, such as a diaper on the skin. 

Blistering often affects the mouth and mucous membranes, which can impact food intake and dental issues. 

Severe thickening of the skin on the palms and soles is common, often significantly impairing mobility. 

Develops gradually and can limit walking or daily activity.

Tiny white cysts may be present from the first weeks of life. 

Dark pigmented moles often appear in areas of repeated blistering. 

Nails may be thickened, damaged, or missing. 

May require medical treatment to manage.  

May experience growth delays, likely due to feeding issues, energy demands of wound healing, and chronic inflammation. 

In the neonatal period, large, tense blisters and congenital ulcerations are common. The condition may be life-threatening in infancy due to extensive skin damage and related complications.

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.