Repeated blistering and excessive scarring on hands and feet may result in total encasement of digits and acral mitten deformities (pseudosyndactyly) which is a clinical hallmark of recessive dystrophic EB (RDEB-gen sev; RDEB-inversa [RDEB-I]; infrequently in dominant DEB and rarely observed in generalized severe junctional EB) (Fig. 42.2) [2, 3]. Pseudosyndactyly initially presents as partial fusion (proximal webbing-adhesion, synechiae formation) within the interdigital spaces and is followed by progressive bridging and complete fusion of all of the individual digits to a keratinaceous cocoon-like, scarred mass (mitten deformities). Contractures of fingers, toes, hands (adduction contractures of thumb), and feet begin to develop as early as within the first year of life in RDEB-gen sev and RDEB-I (infrequently in DDEB). Also proximal contractures may occur, especially within the popliteal and antecubital fossae and axillary vaults. Muscle atrophy, bone absorption, and progressive functional disablement (difficulties in weight bearing, standing, walking; reduced fine manipulative skill; loss of digital prehension) including wheelchair dependency are dramatic sequelae.

Involvement of the nail apparatus causes peri- or subungual blistering, hemorrhages, and nail bed hyperkeratosis with onycholysis and onychomadesis. Early nail dystrophy and loss are triggered by trauma (thus, great toenails are more often severely affected) and correlate with disease severity and progression [4]. Symptoms are often just a mild cosmetic problem, but sometimes also the cause of severe disability. Periodic nail shedding and regrowth results in progressive onychodystrophy (shortened, thickened, dome-shaped, yellow-brown nail plate) and onychogryphosis (thickened, opaque, yellow, oyster-like nail plate). Mitten deformities, nail atrophy (very thin, brittle, short), and, ultimately, complete loss due to nail bed and matrix damage by repetitive blistering and scarring occur.

Increased hair fragility and sparse hair as well as scarring alopecia secondary to trauma, blistering, and/or infections involving interfollicular epidermis and upper portions of the hair follicle are constant features of RDEB-gen sev that are further aggravated by traction [5]. Anemia and sepsis may account for a telogen effluvium.

EB nevi are a frequent phenomenon in RDEB-gen sev as in other types of EB. They develop as most common acquired melanocytic nevi, beginning as flat, black to brown pigmented lesions, which later, while acquiring dermal components, lose their pigment (Fig. 42.3). Gradually appearing in infancy or adolescence as stippled maculae, these moles develop papillomatous areas over years, resulting in dermal shagreen-like nevi [6]. EB nevi typically arise in sites of previous bullae or erosions, often with a darker rim at the confines of the preceding vesiculation. This led to the hypothesis that pathogenetically the repetitive disruption of the basement membrane primes local nevus cell nests or single melanocytes to break senescence and undergo proliferation [7, 8]. Viable melanocytes/nevus cells, probably deriving from incipient nevi or subclinical nests of nevus cells, free-float in the fluid-filled cavity of EB blisters (“flocking-bird melanocytes”) and, after settling down at random (often trapped in the sharp angel at the edge of the blister), proliferate excessively in the microenvironment of epidermal regeneration (involving cytokines and growth factors such as hepatocyte growth factor, interleukin-8, granulocyte-macrophage colony-stimulating factor, prostaglandin E2 or leukotriene B4) [9]. The arbitrary arrangement of independently proliferating melanocytic clones and enhancing secondary changes due to wound healing, scar formation, disruption of rete ridges, and neovascularization probably account for the irregular appearance of these moles.

Skin-derived squamous cell carcinoma (SCC) is a very common complication of particularly RDEB-gen (> RDEB, generalized intermediate > RDEB-I and JEB) (Fig. 42.4). It is occasionally also observed on the tongue or in the esophagus [2]. Tumors arise most commonly at sites of chronic wounding, regeneration, or scarring and as early as within the second decade of life. Their frequency further increases thereafter. This is complicated by a very aggressive course and extremely high rates of metastasis as well as recurrence. Referring to solid statistics provided by the US National EB Registry, metastatic SCC is the primary cause of death in RDEB, occurring in the majority of patients with RDEB-gen sev. The cumulative risk of developing SCC and subsequent death in patients with RDEB-gen sev at age 55 is greater than 90 and 78 %, respectively [17, 18].

In RDEB-I, blistering is predominantly located in intertriginous but also lumbosacral, acral, and axial areas. Further observed are nail dystrophy; involvement of oral cavity and gastrointestinal and genitourinary tract; stenosis of meatus acusticus externus; anemia; and growth retardation.

Pretibial RDEB is characterized by pretibial blistering at birth or early infancy, involvement of hands and feet, lichen planus-like skin lesions, nail dystrophy [may precede skin blistering], excessive caries, and constipation. It may be associated with localized cutaneous amyloid deposition derived from degenerated keratinocytes secondary to scratching or induced by damage to epidermal-dermal junction/blister formation. Presenting with fragile blisters and erosions that are often overshadowed by pruritic lichenified plaques, this variant is often misdiagnosed as lichen amyloidosis [21].

Localized RDEB presents with blistering on hands and feet from early infancy on. Nail dystrophy is described.

RDEB pruriginosa: generalized or localized blisters, erosions, milia, and atrophic scars usually from infancy on, folliculitis-like lesions on scalp [22], and nail dystrophy. Excessive pruritus on a background of inherited skin fragility leads to skin signs resembling acquired inflammatory disorders such as hypertrophic lichen planus or prurigo nodularis; onset may not occur until adult life, further compounding difficulties in distinguishing between inherited or acquired skin disorders [23].

RDEB centripetalis: pretibial and acral blistering at birth or from early infancy on, nail dystrophy, and involvement of oral mucosa.

RDEB: bullous dermolysis of the newborn which presents with generalized blistering from birth or early infancy on, milia, atrophic scarring, and dystrophic nails.

Nail abnormalities with dystrophy or loss at birth or infancy may be an isolated finding as reported in DDEB [26, 27]. This “nails-only DDEB” variant is a newly recognized subtype of DEB, in which nail dystrophy is the only clinical feature (Fig. 42.7). The deformity is often limited to the toenails and can be mild and thus easily overlooked. Moreover, nail involvement without blistering may be present for generations before a DEB family member develops blisters in the skin. Diagnosis should thus be considered in patients with an autosomal dominant trait of toenail dystrophy, even when there is no history of blistering [28].