Epidermolysis bullosa simplex (EBS) is an inherited skin disorder characterized by separation of the epidermis from the underlying dermis, with the cleavage plane lying within the basal-cell layer of the epithelium. The major clinical subtypes of EBS have a dominant inheritance and have been associated with genetic defects in specific domains of keratins K5 and K14 that result in abnormal organization of the keratin network and cell disruption. Autosomal recessive forms of EBS associated with extracutaneous manifestations, such as muscular dystrophy (MIM 226670) or pyloric atresia (MIM 612138), have been linked to genetic mutations in the gene for plectin ( PLEC ). PLEC mutations have also been found in 2 families with the rare dominant Ogna form of EBS. This article reviews current knowledge on EBS.
Epidermolysis bullosa simplex (EBS) is an inherited skin disorder characterized by separation of the epidermis from the underlying dermis, with the cleavage plane lying within the basal cell layer of the epithelium. The major clinical subtypes of EBS have a dominant inheritance and have been associated with genetic defects in specific domains of keratins K5 and K14 that result in abnormal organization of the keratin network and cell disruption. Autosomal recessive forms of EBS associated with extracutaneous manifestations, such as muscular dystrophy (EBS-MD) (MIM 226670) or pyloric atresia (EBS-PA) (MIM 612138), have been linked to genetic mutations in the gene for plectin ( PLEC ). PLEC mutations have also been found in 2 families with the rare dominant Ogna form of EBS. PLEC encodes for plectin, a versatile cytoskeletal linker protein abundantly expressed in several cell types. Plectin is associated with intermediate filaments, and various subplasma membrane–cytoskeleton and membrane-cytoskeleton junctional complexes in epithelia, muscles, and fibroblasts. Consistent with its numerous binding partners, plectin mutation results in pleiotropic phenotypes.
EBS with MD
Patients reported in literature with EBS-MD are usually born at term after an uneventful pregnancy ( Table 1 ). Consistent with an autosomic recessive inheritance, parents are often found to be related and are asymptomatic. At birth or soon after (15 days) the affected newborn develops blisters and erosions on the extremities, the back, and the face, which recur at the sites of mechanical trauma. Blisters are tense and can be hemorrhagic. Healing occurs without scarring but occasionally with mild residual atrophy. No congenital cutis aplasia (CCA) is present. One patient developed a few milia on the fingers. In all cases, no improvement of skin involvement has been described with time and skin fragility seems to be mild. Nail involvement is constant, with congenital onychodystrophy (pachyonychia) of the fingers and toes, although loss of nails is uncommon ( Fig. 1 ). Four patients had a focal plantar hyperkeratosis with crusted lesions. Dental anomalies such as premature tooth decay have been reported in 64% of cases. Some patients have presented from a few months of age with severe mucous membrane involvement with a hoarse cry, episodes of inspiratory stridor, recurrent and severe respiratory tract infections, and occasional bouts of severe respiratory insufficiency caused by swelling of the laryngeal mucosa. Laryngoscopic examination typically reveals blisters, erosions, and strictures of epiglottis and laryngeal mucous membranes with fusion of the arytenoid cartilages; the appearance of the infraglottic airway is normal. Oral lesions were noted in only 1 case and involved the tongue in particular, but clinical descriptions of patients are not always clear. Treatment of the laryngeal complications required a tracheotomy for 3 patients varying in age from 20 months to 3 years; for another patient, repeated balloon dilatations led to stabilization of respiratory problems. One patient also had urethral strictures in infancy and another patient had only urethral stricture without oral involvement. The presence of severe mucous lesions does not indicate an early onset of MD, but all patients with an early onset of MD have mucous involvement. No ophthalmologic findings have been reported and hair has been described as normal, although 2 patients had partial congenital alopecia of the scalp.
|Patient||Sex/Age (Years)||Consanguinity||Origin||Skin Involvement||Muscle Involvement||Other||Mutations||Refs.|
|Age Onset||Mucosa||Nail||Teeth||Focal Plantar Keratodermy||Age of Onset (Years)||Evolution||Mutation 1||Type||Exon||Mutation 2||Type||Exon|
|P2||M/33||0||Malta||Birth||1||1||NA||0||2||Cerebral and cerebellar atrophy||R2465X||ptc||32||R2465X||ptc||32|
|P3||F/10||1||Italy||Neonatal||1||1||NA||0||0 at 10||(5905del2) |
|P5||M/24||1||Spain||Neonatal||0||1||1||0||10||Unable to walk age 13||(5148del8) |
|P9||F/46||1||Japan||Neonatal||0||1||0||0||30||Able to walk and carry out routine activity||(2719del9) |
|In-frame del3aa||22||(2719del9) |
|P10||M/38||0||Japan||Neonatal||1||1||1||0||30||Unable to walk in mid-30s||(5866delC) |
|P11||F/5.5||1||England||Birth||1||1||0||1||0 at 5,5||(5069del19) |
|P12||M/40||0||NA||Neonatal||1||1||1||0||20||Considerable muscle weakness||(4416delC) |
|P13||M/9||1||Japan||Birth||1||1||1||0||Infancy||Major difficulties in walking at 9||Partial scarring alopecia||Q1936X||ptc||32||(Q1053X) |
|P14||M/33||0||Japan||Neonatal||0||1||1||0||5||Unable to walk at 22||Partial scarring alopecia||R2421X||ptc||32||(12633ins4) |
|P16||F/52||0||Japan||Birth||0||1||1||0||25||Unable to walk age 46||R2319X||ptc||32||R2319X||ptc||32|
|P19||F/5 months||France||Neonatal||1||NA||1||0–5 months||(2745-9 del21) |
|In-frame del7aa||22||(5083delG) |
|P22||M/6 months||Spain||Birth||0||1||0||0||0–6 months||Extensive cleft lift and palate||E2005X||ptc||32||K4460X||ptc||33|
|P23||M/4||White||Birth||0||1||0||0||0–6 years||1287ins3*/ |
|P24||F/25||White||Birth||0||1||0||0||11 years||Facial weakness, ptosis, exophthalmia, dysphonia, weakness, and atrophy of trunk and limbs||Mental retardation, bilateral cataract, cardiac hypertrophy, MAV left leg, cerebral atrophy||(13803ins16) |
|P25||NA||NA||NA||NA||NA||NA||NA||42 years||1541ins36*||In-frame ins12aa||14||(677del9) |