Clinical Guidance

Limited genotype-phenotype correlations have been reported. Digenic inheritance adds further complexity to genotype-phenotype associations observed in EBS . KRT5 and KRT14. A moderate correlation exists between the EBS phenotype and the functional domain of either KRT5 or KRT14 in which the pathogenic variant is located [, , , ]. Phenotypic expression can be highly variable; localized EBS, intermediate EBS, and severe EBS phenotypes have been reported in affected individuals from the same family .

Source: GeneReviews — "Epidermolysis Bullosa Simplex"

Penetrance

Penetrance is 100% for biallelic KRT5 and KRT14 loss-of-function variants but appears to be less than 100% for heterozygous dominant-negative variants, as rare heterozygotes for dominant-negative variants are asymptomatic . Heterozygous pathogenic variants in PLEC and KLHL24 and biallelic pathogenic variants in CD151, DST, EXPH5, and PLEC are presumed to be fully penetrant as asymptomatic individuals have not been reported to date.

Source: GeneReviews — "Epidermolysis Bullosa Simplex"

Diagnostic Criteria

Suggestive Findings

Epidermolysis bullosa simplex (EBS) should be suspected in individuals with the following clinical findings:

• Fragility of the skin manifested by blistering with little or no trauma, which typically heals without scarring

• Blistering that:

• May be present in the neonatal period

• Primarily affects the hands and feet but can affect the whole body

• Occurs in annular or curvilinear groups or clusters

• Can lead to progressive hyperpigmentation interspersed with hypopigmented spots on the trunk and extremities that frequently disappears in adult life

• Is associated with palmar and plantar hyperkeratosis that may be severe

• Nail dystrophy

• Milia

• Natal teeth

Establishing the Diagnosis

The diagnosis of EBS is established in a proband with one or both of the following :

Source: GeneReviews — "Epidermolysis Bullosa Simplex"

Differential Diagnosis

The 2020 classification system names four major types of epidermolysis bullosa (EB):

• EB simplex (EBS)

• Junctional EB (JEB)

• Dystrophic EB (DEB)

• Kindler syndrome

All forms of EB are characterized by increased skin fragility (and often mucosa) and blistering with little or no trauma. Classification into major type is based on the location of blistering in relation to the dermal-epidermal junction of skin. Subtypes are predominantly determined by clinical features and supported by molecular diagnosis .

Table 6.

Clinical Features Observed in the Four Major Types of Epidermolysis Bullosa

Feature | Comment

Easy fragility of skin ( often mucosa) manifested by blistering w/little or no trauma | Shared by 4 major EB types

Source: GeneReviews — "Epidermolysis Bullosa Simplex"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with epidermolysis bullosa simplex (EBS), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 8.

Recommended Evaluations Following Initial Diagnosis in Individuals with Epidermolysis Bullosa Simplex

System/Concern | Evaluation | Comment

Skin | • Consultation w/dermatologist to evaluate sites of blister formation

• Assess for signs/symptoms of wound infection.

|

Assess for dehydration (fluid electrolyte disturbances) as needed. | Fluid electrolyte disturbances can be life threatening in neonatal period in infants w/widespread disease.

Oral mucosa

| • Assess for involvement of oral mucosa.

• Assess feeding growth in those w/oral disease.

• Refer to feeding therapist or consider nutritional interventions incl feeding supplementation gastrostomy tube placement if indicated.

| Dental caries are common. Early referral for eval by experienced pediatric dentist may be helpful.

Nutrition

growth | • Assess need for vitamin mineral supplementation incl assessment for anemia.

• Assess weight gain.

|

Physical activity

mobility | • Assess footwear for mobility issues.

• Referral to PT as needed

|

Other

| Referral to neurologist, cardiologist, /or nephrologist as needed for rare manifestations of EBS |

Genetic

Source: GeneReviews — "Epidermolysis Bullosa Simplex"

Clinical Guidance

Excessive heat and sweating may exacerbate blistering, wounding, and infection in EBS. Poorly fitting or coarse-textured clothing and footwear can cause trauma and should be avoided. Avoiding activities that traumatize the skin (e.g., hiking, mountain biking, contact sports) can reduce skin damage; however, affected individuals who are determined to find ways to participate in these endeavors should be encouraged. Many individuals with EBS cannot use medical tape or Band-Aids® with adhesives.

Source: GeneReviews — "Epidermolysis Bullosa Simplex"

Therapies Under Investigation

Proposed approaches for gene therapy in EBS include the use of CRISPR/Cas9-mediated DNA repair , TALEN-mediated DNA repair , viral vectors carrying corrected gene products to transduce keratinocytes , RNA trans-splicing repair , addition of other functional proteins , induction of a compensating pathogenic variant via revertant mosaicism , and pathogenic variant-specific siRNAs . Systemic gentamicin may also induce PLEC readthrough and increase plectin expression in individuals with EBS, intermediate with muscular dystrophy caused by pathogenic nonsense variants . To date, however, no clinical trials of gene therapy for EBS have been completed.

Source: GeneReviews — "Epidermolysis Bullosa Simplex"

Surveillance Guidelines

Table 9.

Recommended Surveillance for Individuals with Epidermolysis Bullosa Simplex

System/Concern | Evaluation | Frequency

Skin | • Dermatologic assessment for blisters, oral disease, hyperkeratosis, hyperhidrosis, signs/symptoms of wound infection, pain, itching

• Assess hydration status.

| At each visit

Growth, weight,

nutrition | Assess growth nutritional status, incl poor or excess weight gain, feeding issues, signs/symptoms of anemia dietary deficiencies.

Motor

development

mobility | Assess effect of skin disease on motor skills functional mobility, incl walking.

Psychosocial

well-being | Assess psychosocial well-being quality of life.

Cardiac

| In persons w/EBS, intermediate w/cardiomyopathy: consider serum BNP creatinine kinase due to risk for early-onset dilated cardiomyopathy.1 | As needed /or as recommended by cardiologist

Other

| • Neurologic assessment for those w/muscular dystrophy

• Nephrology assessment for those w/nephropathy

| As needed /or as recommended by relevant specialist

BNP = B-type natriuretic peptide

1. , ,

Source: GeneReviews — "Epidermolysis Bullosa Simplex"