The range in severity in EB simplex.

This post is dedicated to Inez Elizabeth Raquel Ontiveros Jaime who lost her battle to EB Simplex while I was composing this post.  

When people hear the term EB simplex, they likely of someone with mild blisters on their hands and feet.  Nothing serious, nothing compared to the other more severe forms of EB.  

And while simplex, is milder than some of the other forms of EB, the range in severity can vary GREATLY from very mild to very severe.  The purpose of this post is to show the serenity within the umbrella of EB simplex.  I am NOT comparing it to other forms of EB. 

These are dominant forms of EB Simplex

 

EB Simplex- Localized  (formally known as Weber-Cockayne)

Per the Genetic and Rare Disease Website: Onset is usually in late infancy or early childhood. The usual distribution of blisters in these patients is on the palms and soles, although other skin surfaces may also blister if subjected to significant trauma. Milia and scarring are rare in localized EBS, and dystrophic nails are uncommon. Focal keratoderma (thickening) of the palms and soles may occur by adulthood in some patients. The only common extracutaneous finding in localized EBS, i.e. localized oral erosions or blisters, tends to be asymptomatic, occurs in about one third of patients, and is usually seen only during infancy.  EBS-LOC is autosomal dominant and sporadic cases are frequent.  Although the disease can be disabling, life-expectancy is normal.

Those are probably what people picture in their head when they hear the phrase "EB simplex".  Below is what EB simplex can also look like....

*************************************************************

EBS- generalized intermediate  (formerly know as Koebner) 

Per the Genetic and Rare Disease Website: Epidermolysis bullosa simplex, generalized intermediate is associated with widespread blisters that appear at birth or in early infancy.Blisters occur in areas where skin rubs together, or after minor injuries.  Other features of EBS include nail involvement, thickening of the skin on the palms of the hands and soles of the feet, and small bump-like cysts known as milia  The symptoms of this condition can be very different from person to person, ranging from mild blistering of the hands and feet to blistering that occurs all over the body that can be fatal.  This form can either be dominant or recessive in inheritance.

Epidermolysis bullosa simplex (EBS) generalized intermediate that is associated with genetic changes in either the KRT5 or KRT14 genes is inherited in an autosomal dominant pattern.  Epidermolysis bullosa simplex (EBS) generalized intermediate that is associated with genetic changes in either the EXPH5 or TGM5 genes is inherited in an autosomal recessive pattern

 

 **********************************************************

EBS- generalized severe (formerly known as dowling meara) 

Per the Genetic and Rare Disease Website: Onset is usually at birth with large, frequently hemorrhagic blisters. After the neonatal period, the lesions take the typical herpetiform (or herpes-like) clustering with central healing pattern. Blister formation gradually reduces starting from late childhood. By childhood, most patients begin to develop confluent thickening and hyperkeratosis (keratoderma) of the palms and soles which may partially resolve in some patients during mid- to late-adulthood. Along with blisters, skin findings commonly include mild atrophic scarring and post-inflammatory pigmentation, nail shedding and nail dystrophy, as well as occasional milia formation. Lesions may improve in some patients in case of fever, unlike other forms of EB in which warmer weather exacerbates disease activity. The reason for this is unknown. Extracutaneous complications can occur including oral cavity blistering, constipation and, rarely, tracheolaryngeal compromise. 

Transmission is autosomal dominant and sporadic cases are frequent.

EBS- generalized severe is frequently associated with marked morbidity in infancy and early childhood and, in rare cases, may result in death during early infancy. Patients also have a markedly increased risk of basal cell carcinoma by mid-adulthood (cumulative risk of 44% by age 55).

 

******************************************

 

 EBS-KLHL24 subtype

EBS KLHL24 have a characteristic clinical phenotype, showing skin defects and blistering at birth and unusual stellate scarring, skin fragility, and whorled or macular hyperpigmentation or hypopigmentation in childhood. Although skin fragility improves by adulthood, nail dystrophy, anetoderma, and hair loss may occur.  Patients with this type are also at high risk for cardiomyopathy 

 

 ********************************************

 

Now onto the recessive forms of EB: 

 

Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD)

Onset of blistering is usually as early as birth, whereas muscular dystrophy manifests between infancy and adulthood. Blisters are often hemorrhagic and heal with mild atrophic scarring and rare milia formation. Associated findings comprise markedly dystrophic nails, and focal keratoderma of the palms and soles. Extracutaneous involvement is usually present, including enamel hypoplasia with premature tooth decay, blistering in the oral cavity, pharynx and, rarely, larynx and trachea with inspiratory stridor and breathing difficulties requiring tracheotomy. Slowly progressive weakness of the head and limb muscles appears between the first year and the fourth decade of life and may confine the patient to a wheelchair. Additional neurological symptoms (ptosis, oculobulbar muscle weakness and fatigability) indicative of a myasthenic syndrome have been described in some patients.  EBS-MD is caused by mutations in the PLEC gene (8q24) encoding plectin. Plectin deficiency can be demonstrated in skin and muscle by analysis with specific antibodies.

 

 *******************************************

 

Autosomal Recessive EBS- K14 mutation:

• 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.  

   

  
  
  
  
  
  

  
  

Other Rare Types of EBS (info obtained from www.debra.org)

EBS with mottled pigmentation:

• 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.  

   

   **********************************

  EBS with migratory circinate eythema

  • 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. 

  
  

  EBS, localized or intermediate with BP230 deficiency

  • 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. 

  
  

  
  

  EBS, localized or intermediate with exophilin 5 deficiency

  • 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. 
  

• 
  

  
  

  EBS, intermediate with PLEC variants

  • 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.  

  
  

  EBS, severe with pyloric atresia
  

•  

  • 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.
  

• 
  

• EBS, localized with nephropathy w/ CD151 deficiency

  
  

  • 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.

  
  

  
  

  For those that made it this far, THANK YOU for reading this post!!! My purpose is to educate and inform.