Inherited Epidermolysis Bullosa and skin fragility syndromes – Darier disease – Hailey-Hailey disease
Epidermolysis bullosa simplex (EBS)
Epidermolysis bullosa simplex (EBS) is 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.
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 confluent 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 EB subtype. Several subtypes exist based on the intraepidermal localization of blisters. In most, blisters occur in the basal layer of the epidermis (autosomal recessive EBS; Dowling-Meara type; Köbner type; EBS – muscular dystrophy; Ogna type; EBS – pyloric atresia; localized EBS; EBS with migratory circinate erythema; EBS with mottled pigmentation). However, 3 subtypes involve suprabasal blistering (EBS due to plakophilin deficiency, EBS superficialis, lethal acantholytic EB).
Reported prevalence ranges from 1/215,000 in the USA to 1/35,000 in Scotland.
Junctional epidermolysis bullosa (JEB)
Junctional epidermolysis bullosa (JEB) is a form of inherited epidermolysis bullosa characterized by involvement of the skin and mucous membranes, and is defined by the formation of blistering lesions between the epidermis and the dermis at the lamina lucida level of the cutaneous basement membrane zone and by healing of lesions with atrophy and/or exuberant granulation tissue formation.
Onset is usually at birth with the exception of late-onset JEB. Several JEB subtypes have been described based on clinical features. All subtypes are characterized by the presence of enamel hypoplasia manifesting as localized or more extensive thimble-like pitting of some or all of the tooth surfaces. Blistering is usually associated with atrophic scarring or with exuberant granulation tissue formation and nail dystrophy. Additional skin findings may include congenital aplasia cutis congenita and progressive hair loss. Mucosal involvement is constant, although of variable severity, and can affect the gastrointestinal, respiratory and genitourinary tracts and the eyes. Pyloric atresia is the hallmark of the JEB with pyloric atresia subtype. JEB is divided in two major subtypes: the more severe JEB-Herlitz form and the JEB-other subtype which in turn comprises six variants, the last 3 of which are very rare (JEB, non Herlitz, generalized; JEB, non-Herlitz, localized; JEB with pyloric atresia; JEB inversa; late-onset JEB; LOC syndrome).
JEB is the less common, but frequently early lethal form of EB. Incidence data from the U.S. and Italian EB registries indicate 1/450,000 and 1/260,000 live births, respectively.
Dystrophic epidermolysis bullosa (DEB)
Dystrophic epidermolysis bullosa (DEB) is a form of inherited epidermolysis bullosa (EB) characterized by cutaneous and mucosal fragility resulting in blisters and superficial ulcerations that develop below the lamina densa of the cutaneous basement membrane and that heal with significant scarring and milia formation. It comprises ten sub-types with the three most common being generalized dominant DEB (DDEB), severe generalized recessive DEB (RDEB- sev gen) and RDEB generalized-other.
The clinical picture varies widely, ranging from mild to severe. Onset is usually at birth but a delayed onset in infancy, childhood or adolescence can also be observed. Skin lesions, forming spontaneously or in response to friction, may show a generalized or a localized distribution, particularly on the hands, feet or pretibial areas. Healing of blisters is associated with atrophic or, more rarely, hypertrophic scarring, albopapuloid lesions, milia formation and dystrophic nails. Excessive scarring can lead to highly disabling hand/foot deformities (”mitten deformities” typical of RDEB- sev gen). Mucosal involvement is common and most frequently manifests with oral cavity lesions and esophageal strictures. The eyes and the genitourinary tract can also be affected. Skin and mucosal involvement can lead to anemia, iron deficiency and growth delay. DEB patients are also at a higher risk of occurrence of squamous cell carcinomas (SCC).
DEB is the second most common form of EB, the first being EB simplex. The overall reported prevalence varies from 1/49,000 inhabitants in Scotland to 1/420,168 in the United States.
Kindler syndrome (KS)
Kindler syndrome (KS) is the fourth major type of epidermolysis bullosa (EB), besides simplex, junctional and dystrophic forms, and is characterized by skin fragility and blistering at birth followed by development of photosensitivity and progressive poikilodermatous skin changes.
The disease usually manifests at birth with trauma-induced skin blistering that is more prominent on extremities and tends to regress with age, becoming rare in adulthood. Healing of blisters occurs with minimal scarring. With age, additional skin findings are observed: (i) in most patients, photosensitivity with erythema and photo-induced blisters is obvious since early childhood and often diminishes after adolescence, (ii) progressive skin poikiloderma (atrophy, telangiectases, and reticular pigmentation) manifests from childhood and is predominantly localized to the face and neck, and (iii) skin atrophy is localized to hands and feet in the first years of life but becomes generalized by adolescence. Blisters also affect the mucosae. In the oral cavity, chronic gingivitis and periodontitis are frequent and prominent features in adulthood. Esophageal strictures, causing dysphagia and requiring repeated dilatations, frequently develop in adulthood. Anal (bleeding, stenosis), urogenital (urethral bleeding, meatal stenosis), and ocular (ectropion) involvement has also been described. The frequency of these manifestations increases with age. An additional frequent feature is digit webbing/partial pseudosyndactyly. Laryngeal and intestinal involvement, the latter manifesting with severe colitis, are rare. Other features may include: skin xerosis and fine scaling, palmoplantar hyperkeratosis, milia formation, nail dystrophy, constricting bands of pseudoainhum type, orogenital leukokeratosis. Finally, KS patients present an increased susceptibility to the development of squamous cell carcinomas (SCC): in a recent case series skin cancer affected 70% of the patients older than 45 years. Prevalence is unknown. More than 250 cases have been reported to date.