Epidermolysis bullosa simplex (ORPHA:304)
A group of hereditary epidermolysis bullosa (HEB) disorders characterized by skin fragility resulting in intraepidermal blisters and erosions that occur either spontaneously or after physical trauma.
Epidemiology
Reported prevalence of epidermolysis bullosa simplex (EBS) ranges between 1/85,000-500,000 worldwide.
Clinical description
Onset is usually at or shortly after birth, although blistering in localized EBS may not develop until late childhood or early adulthood. Along with localized or generalized blistering and erosions, sometimes showing characteristic patterns (herpetiform grouping), cutaneous features may include nail shedding and dystrophy, and, rarely, milia formation. Scarring is mostly absent or minimal (mild atrophic wrinkling and dyspigmentation). Other findings may include congenital absence of the skin, and localized or diffuse keratoderma of the palms and soles. The commonest extracutaneous manifestation is blistering of the oral cavity. A variety of additional extracutaneous complications may occur and are age-dependent, with time of onset and cumulative risk of occurrence highly dependent on the EBS subtype (e.g. muscular dystrophy in PLEC-related EBS, cardiomyopathy in KLHL24-related EBS, nephropathy in CD151-related EBS). Blisters occur in the basal layer of the epidermis.
Etiology
EBS is a genetically heterogeneous group caused by pathogenic variants in specific genes depending on the subtype.
Diagnostic methods
Diagnosis is based on determination of the epidermal level within which blisters develop following minor skin traction. Recommended techniques are immunofluorescence antigen mapping (IFM) and transmission electron microscopy (TEM) performed on a skin biopsy sample. Subtypes are then defined on the basis of the mode of transmission, IFM and TEM, and clinical presentation. Cutaneous findings are not reliable diagnostic markers, in particular in neonates. Genetic testing should always be performed to determine the underlying genetic defect. Because of the genetic heterogeneity, analysis by next generation sequencing EB-gene panel is recommended.
Differential diagnosis
Diagnosis is usually straightforward with little need for extensive differential diagnosis. However, in the neonatal period, in utero herpes simplex infection may be considered, especially if there is no family history of blistering disease or if clinical findings are atypical for epidermolysis bullosa. The differential diagnosis in neonates and small children may include congenital aplasia cutis, neonatal pemphigus, neonatal herpes gestationis, staphylococcal scalded skin syndrome, as well as incontinentia pigmenti, epidermolytic ichthyosis, linear IgA dermatosis, bullous pemphigoid, and bullous impetigo.
Antenatal diagnosis
Prenatal diagnosis should be offered to families with severe EBS.
Genetic counseling
In autosomal dominant EBS subtypes, affected individuals have an affected parent from whom they inherited a pathogenic variant, but in a high percentage of cases, pathogenic variants occur de novo. Each child of an individual with EBS has a 50% risk of inheriting the pathogenic variant. In autosomal recessive EBS subtypes, the parents of an affected child are obligate heterozygotes for an EBS-related pathogenic variant. Each sib of an affected individual has a 25% risk of being affected, a 50% risk of being heterozygous , and a 25% risk of being unaffected and not heterozygous. Autosomal recessive EBS is common in countries with high rates of consanguineous marriages.
Management and treatment
Management is based on the avoidance of blistering by meticulous protective skin padding and appropriate life-style to avoid trauma, and prevention of secondary infection by careful wound care. Air-conditioning may help in preventing disease worsening in warm weather. Patients with EBS subtypes with the highest risk of specific extracutaneous complications need to be monitored closely and appropriate measures implemented to prevent the affected tissues from becoming severely injured. Topical inhibitors of IL-1 have proven some benefit in small clinical trials. No specific treatment is available for the extracutaneous manifestations of EBS.
Prognosis
Prognosis is highly dependent on the subtype. Most patients have a normal life expectancy but significant morbidity and even early death may occur in some subtypes.

                            Last update: 
                            July 2021


                            - Expert reviewer(s): 
                            Pr Cristina HAS | ERN-Skin*


                                * European Reference Network