Lethal acantholytic EB

Lethal acantholytic EB has been described in two cases with severely defective skin and mucosal epithelia.¹⁹ The disease was lethal in the neonatal period due to epidermolysis that was first noted during parturition leading to uncontrollable loss of fluid from the skin. Additional defects included universal alopecia and complete shedding of nails and the presence of neonatal teeth. Histology revealed clefting of the suprabasal layer producing a tombstone-type appearance reminiscent of pemphigus vulgaris. Molecular investigation revealed that the patient had inherited two different nonfunctional copies of the gene encoding desmoplakin (DSP, a desmosomal protein that links the transmembrane cadherins to the various proteins of the cytoplasmic intermediate filaments), one from each parent, indicating that the disease is autosomal recessive. The mutations both lead to truncation of the desmoplakin protein and an inability to act as a linker. Additional cases will be necessary to further define this syndrome.

Plakophilin deficiency (ectodermal dysplasia-skin fragility syndrome, McGrath syndrome)

Plakophilin is a required component of desmosomes and an important protein in ectodermal development. The rare deficiencies in this protein result in a recently described inherited disease known as ectodermal dysplasia-skin fragility syndrome. Plakophilin-1 (PKP1) deficiency is an autosomal recessive disease that is associated with skin fragility and an inflammatory response resulting in erosions, scale-crust, and progressive palmoplantar keratoderma. Ectodermal effects such as sparse hair and anhidrosis and astigmatism are also noted.²⁰ While initially described in a single child, approximately ten cases with mutations in this gene have now been described.^20,21

Epidermolysis bullosa simplex superficialis

This rare form of EB transmitted in an autosomal dominant fashion was first described in 1989. It specifically differs from the other simplex variants by the site of epidermal cleavage: variable subcorneal split between the stratum corneum and granular cell layer or sometimes within the stratum spinosum rather than intrabasal.²² Patients present at birth or within the first 2 years of life with erosions and crusts sparing the palms and soles. Atrophic scarring, nail dystrophy, and milia are additional common features; oral and ocular epithelia can be affected.²³ As well as the cutaneous manifestations, anemia and gastrointestinal lesions affect a minority of patients. Some cases are associated with mutations causing structural dysfunction of type VII collagen.²³ The condition may be clinically confused with peeling skin syndrome but in the latter there are no blisters and peeling is continous and spontaneous.

EB simplex, localized (Weber-Cockayne; EB simplex of the hands and feet)

This is the most common form of epidermolysis bullosa and has an autosomal dominant mode of inheritance.^{4 5} Lesions are limited to the palms and soles and are usually detected in infancy or the first few years of life (Fig. 4.9). Occasionally, in patients with mild involvement, blisters and erosions may not develop until childhood or even early adulthood in association with strenuous activity. The lesions, which sometimes heal with atrophic scarring, show seasonal variation, often occurring only in the summer months. Hyperhidrosis may sometimes be present. Milia, atrophic scarring, and nail dystrophy are uncommon features.^5,7 The teeth are uninvolved and there is no evidence of any systemic involvement, except perhaps for oral erosions, which may affect an appreciable number of patients in infancy.⁷ Ocular lesions are not a feature. Repeated episodes of secondary infection may occur in some patients. Postinflammatory hyper- and hypopigmentation may sometimes be a cosmetic problem.⁸

Fig. 4.9 EB simplex (Weber-Cockayne): typical lesions affecting (A) the fingers and (B) the toes. The pale color of the latter is due to the marked thickness of the roof of the blister.

By courtesy of the Institute of Dermatology, London, UK.

EBS, Dowling-Meara (EBS herpetiformis)

This variant, which is the second commonest form of EB simplex, shows clinical features resembling dermatitis herpetiformis and has an autosomal dominant mode of inheritance (Fig. 4.10).^7,24–27 Herpetiform grouping of blisters is characteristic. Lesions are usually present at birth and have a distribution sometimes mimicking severe dystrophic or junctional disease.⁷ Some patients die in early infancy due to infection, fluid loss or electrolyte imbalance.¹ Milia formation is common, but atrophy and scarring are rare.⁷ Distal flexural contractures are occasionally present.²⁵ Nail dystrophy is often found and palmoplantar keratoderma is characteristic. Anodontia and hypodontia have also been described. Normalization during episodes of high fever is a typical finding but seasonal variation is not a feature.²⁶ Blistering significantly improves with advancing years.²⁷ Mutations in keratins 5 and 14 underlie this disease.^28–31 Death as a result of complications of the disease is rare and generally occurs by age 1 as a result of sepsis or respiratory failure.³²

Fig. 4.10 EB bullosa simplex: Dowling-Meara variant showing characteristic grouping of blisters and erosions.

By courtesy of R.A.J. Eady, MD, Institute of Dermatology, London, UK.

EBS, other generalized (includes Koebner variant)

This group has an autosomal dominant mode of inheritance and includes primarily those cases previously termed Koebner-type and all other generalized subtypes of EBS.⁵ In the Koebner variant, blisters are present at birth or shortly thereafter and, although the entire body may be affected, lesions are particularly severe on the extremities, where the dorsal surfaces tend to be involved (Fig. 4.11).⁵ The blisters usually heal without scarring or atrophy and milia are very uncommon.⁵ The eruption often worsens in the summer months. The nails are rarely dystrophic and teeth abnormalities are typically absent. Although oral lesions may be present in infancy, systemic involvement is not a feature of this variant.

Fig. 4.11 EB simplex (Koebner): intact blisters are present in the axilla and on the chest.

By courtesy of M.J. Tidman, MD, Guy’s Hospital, London, UK.

EBS with mottled pigmentation

This autosomal dominant variant was originally described in six members of a single kindred.³³ The cutaneous lesions are similar to the Dowling-Meara variant with the addition of mottled or reticulate pigmentation, particularly affecting the neck and trunk. Atrophic scarring, milia, and nail dystrophy are uncommon. Punctate keratoderma affecting the palms and warty hyperkeratotic lesions involving the hands, elbows, and knees may be additional features.^33–35 Dental caries is also sometimes present and intraoral lesions are occasionally seen.

EBS with muscular dystrophy (pseudojunctional EB)

This is an autosomal recessive variant in which patients concomitantly develop muscular dystrophy or exceptionally myasthenia gravis and even cardiac involvement.^36–38 Blisters and erosions present at birth or soon thereafter and are usually generalized. Patients may also suffer from atrophic scarring, milia, nail dystrophy or anonychia, alopecia, and oral lesions^36,37 Severe mucose membrane involvement is rare.³⁹ The mortality of this variant is high.⁶ Mutations in plectin are associated with these forms of the disease.^40–42 Plectin is a large (greater than 500 kD) intermediate filament binding protein that provides mechanical rigidity to cells by acting as crosslinking adaptor to the cytoskeleton.⁴³ The PLEC1 gene bears a domain structure similar to BPAG1, indicating they belong to a common family and may have similar functions.

A lethal variant of EBS with mutations in plectin at the level of the plakin domain may occur exceptionally and it is associated with aplasia cutis of the limbs and developmental impairment.⁴²

EBS with pyloric atresia

This category was placed in the provisional hemidesmosomal category in the prior edition of this book. Cases with pyloric atresia are currently considered in two groups: EBS discussed here, and another category in junctional EB discussed below. This is a rare variant of epidermolysis bullosa in which affected infants are at risk of ureterovesical junction obstruction with fibrosis involving the entire urinary tract and aplasia cutis congenita in addition to pyloric atresia (Figs 4.12, 4.13).^44–47 Polyhydramnios is also seen. The pyloric atresia may be due to a diaphragm or stenosis (Fig. 4.14). The mortality rate of this variant is very high, up to 78% of affected infants succumbing.⁴⁶ It appears to be the most lethal form in the EBS category. Mutations in both plectin and α₆β₄ integrin subunits (junctional EB) have been described.⁴⁸ Since both α₆β₄ integrin and plectin are expressed in villous trophoblast from the first trimester of pregnancy this feature has been used successfully for the prenatal diagnosis of this group of conditions.⁴⁹

Fig. 4.12 EB with pyloric atresia: stillborn infant with widespread blistering.

By courtesy of M.J. Tidman, MD, Institute of Dermatology, London, UK.

Fig. 4.13 EB with pyloric atresia: in addition to blistering there is also deep ulceration.

By courtesy of M.J. Tidman, MD, Institute of Dermatology, London, UK.

Fig. 4.14 (A, B) EB with pyloric atresia: pyloric canal is obliterated by fibrous connective tissue.

EBS, autosomal recessive

Autosomal recessive EBS is generalized with onset at birth. Blistering is prominent with mild atrophic scarring. Ichthyotic plaques and focal palmoplantar keratoderma are sometimes encountered. Nails may be dystrophic or absent. Anemia, growth retardation, dental caries, and constipation can be complications.⁹ Mutations in keratin 14 underlie this disease; keratin 5 mutations have not been described.^50,51

EBS, Ogna

This form is autosomal dominant and presents at birth. It primarily involves acral sites, but can become widespread. Blistering is prominent and onychogryphosis is common. A tendency to bruise has been described.^9,52 Lack of muscular involvement distinguishes this form of disease from EBS with muscular dystrophy described above; the mutation genotype may be predictive of disease expression.^42,53

Mutations in plectin underlie this syndrome.^39,52

EBS, migratory circinate

This generalized form of EBS presents at birth with an autosomal dominant inheritance pattern. Blistering is very prominent and associated with a migratory circinate erythema and postinflammatory hyperpigmentation.⁹ Mutations in keratin 5 have been described, but none is currently reported in keratin 14.^39,54,55

JEB, non-Herlitz, generalized (generalized non-Herlitz junctional EB, EB atrophicans generalisata mitis, generalized atrophic benign EB (GABEB), hemidesmosomal EB, junctional EB mitis)

This somewhat milder form, in which the cutaneous features are similar to the gravis form, includes some patients with laminin-332 gene mutations and others with mutations in type XVII collagen previously classified in the hemidesmosomal group.^9,62 Systemic involvement is typically mild or absent.^63–66 Patients present at birth with extensive blistering and erosions accompanied by mild scarring and widespread cigarette paper-like atrophy. Variable hyperpigmentation and hypopigmentation are characteristic.⁶³ Skin lesions may be exacerbated during summer. Milia are variably present. Exuberant granulation tissue is less common than in the Herlitz variant. Other features include dystrophic or absent nails (Fig. 4.18), oral erosions with mild scarring, pitted dystrophic enamel, and severe dental caries. Ocular lesions include recurrent corneal erosion, blistering, and corneal scarring.⁶⁴ Follicular atrophy with resultant alopecia involving the scalp, axillary, and pubic hair in addition to sparse eyelashes and eyebrows is common (Fig. 4.19).⁶³ Large or multiple melanocytic nevi have also been described as part of the phenotype⁵⁸ but this is not currently believed to be a specific feature.⁵ Contractures do not develop. Systemic involvement is usually limited to mild laryngeal and/or esophageal lesions.⁴ Growth may be retarded and anemia is present in some patients. Infantile mortality is high (up to 44.7%).^7,32

Fig. 4.18 Generalized atrophic benign EB: there is scarring and complete absence of nails.

By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.19 Generalized atrophic benign EB: note the sparsely distributed eyebrows and eye lashes.

By courtesy of the Institute of Dermatology, London, UK.

JEB, non-Herlitz, localized

This milder and localized form of JEB is associated with mutations in type XVII collagen rather than laminin-332.^67,68 Genotypic correlations and immunofluorescence antigen mapping may allow distinction of this form from the more several generalized form.⁶⁸

JEB with pyloric atresia

All EB with pyloric atresia was previously placed in the now defunct hemidesmosomal category. These cases are now divided into two categories within EBS and JEB. While both plectin and α₆β₄ integrin subunit mutations have been noted in EBS with pyloric atresia, only the latter is believed associated with JEB with pyloric stenosis.^69–71 The clinical features are similar, with generalized blisters present from birth associated with atrophic scarring, dystrophic or absent nails, and milia on occasion. Large areas of aplasia cutis have been described.⁶⁷ This disease is usually fatal at an early age.

JEB inversa

Lesions, which are present at birth or develop in early infancy, are initially generalized, but later are predominantly localized to inverse (flexural) sites including the axillae and groin.⁵ Blisters and erosions are accompanied by atrophic scarring and nails may be dystrophic or absent. Other features that are sometimes evident include mouth erosions, maldeveloped teeth with enamel hypoplasia, and occasional gastrointestinal lesions, particularly affecting the esophagus and anus. Mutations in the subunits of laminin-332 are noted.^9,58

JEB-late onset (progressiva)

In this variant, lesions do not present until late childhood, and consist of blisters and erosions affecting the hands, elbows, knees, and feet.⁵ Nails may be dystrophic or absent and enamel hypoplasia is characteristic. Mouth erosions may be evident. Mild finger contractures are sometimes a complication.^3,5 The mutation underlying this form of the disease is unclear.⁹

Laryngo-onycho-cutaneous (LOC) syndrome

A mutation in the gene encoding the laminin-332 α₃ chain resulting in an unusual N-terminal deletion underlies this syndrome.⁷² It was first described by Shabbir and colleagues in 22 patients of Punjabi extraction and about 10 additional cases have been described.^73,74 So far, this autosomal recessive condition has not been described outside of this population. It can occur in a nonconsanguineous context. It consists of epithelial defects resulting in cutaneous erosions, nail dystrophy, and chronic conjunctival and laryngeal granulation tissue. Symblepharon and blindness are serious complications. Airway obstruction and infection can also be problematic. The degree of skin fragility is less than that seen in other variants of JEB. Under the new classification system, based on molecular and clinical similarities to JEB, this syndrome has been added as a rare variant.^9,59

Dominant dystrophic EB, generalized

Autosomal dominant EB, generalized includes both the Cockayne-Touraine and Pasini variants. This is because the two conditions are characterized by identical type VII gene mutations and the albopapuloid lesions (white perifollicular papules and plaques) have been found to be an inconsistent finding (Fig. 4.20).^6,7 Generalized blisters are seen at birth (Fig. 4.21a).^4,8 Alopecia may be present and milia, atrophic scarring, and dystrophic or absent nails are typical features (Fig. 4.21b). Oral involvement may be mild or absent. Enamel hypoplasia is sometimes evident. Gastrointestinal and genitourinary tract involvement is seen in a minority of patients. There is a slightly increased risk of basal cell carcinoma and melanoma.⁷⁵

Fig. 4.20 Dystrophic EB: albopapuloid lesions on the lumbosacral area. These are an inconstant finding in dystrophic EB. The lesions are not preceded by blistering and probably represent connective tissue nevi.

By courtesy of M.J. Tidman, MD, Guy’s Hospital, London, UK.

Fig. 4.21 Dominant dystrophic EB (Cockayne-Touraine): (A) truncal involvement is present in addition to the more typical limb lesions; (B) hemorrhagic blisters, scarring, milia and nail dystrophy.

By courtesy of the Institute of Dermatology, London, UK.

Dominant dystrophic EB, acral

In this mild autosomal dominant localized variant, lesions present at birth or in early childhood, particularly in an acral distribution. Blisters and erosions in the absence of other significant lesions except for atrophic scarring, milia, and nail dystrophy may cease altogether after childhood.¹ Extracutaneous manifestations have not been recorded.

Dominant dystrophic EB, pretibial

This is a mild, localized, and typically symmetrical autosomal dominant form. An autosomal recessive variant has recently been described (see below).⁷⁶ The onset is often delayed, patients usually presenting in early childhood.⁷⁷ Blisters and erosions accompanied by atrophic scarring and milia are particularly seen on the pretibial region and dorsal aspects of the feet (Figs 4.22, 4.23). The scarring may have a violaceous appearance reminiscent of hypertrophic lichen planus.⁷⁶ Lesions are also sometimes seen on the forearms and trunk.⁷⁶ Pruritus and nail dystrophy are common. There are no teeth or hair changes.⁷⁷

Fig. 4.22 Dystrophic EB–pretibial: extensive erosions with scarring are localized to the front of both shins.

By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.23 Dystrophic EB–pretibial: close-up view.

By courtesy of the Institute of Dermatology, London, UK.

Dominant dystrophic EB, pruriginosa

This variant, which presents in childhood, includes dominant and recessive variants (see below).⁷⁸ Patients present with highly pruritic, violaceous nodular prurigo-like nodules developing against a background of blisters, milia, nail dystrophy, and albopapuloid lesions.

Dominant dystrophic EB, bullous epidermolysis of the newborn

This exceptionally rare, self-limiting condition presents in the newborn with blisters that usually resolve within the first 2 years and heal with mild atrophy, milia, and scarring.^79,80 Most cases have been inherited as an autosomal dominant, although recessive variants have also been documented.⁶

Recessive dystrophic EB, severe generalized (Hallopeau-Siemens; polydysplastic EB; EB gravis)

This autosomal recessive variant is a much more serious form than its autosomal dominant counterpart.^4,8 Blisters and erosions are present at birth and, atrophy, scarring, anemia, and growth retardation are consistently present (Figs 4.24, 4.25). Nikolsky’s sign is positive. Destructive involvement of the distal peripheries results in contractures and severe deformities including the characteristic ‘mitten lesions’ (pseudosyndactyly) of the hands and feet (Figs 4.26–4.28).⁸¹ If the latter is left untreated, there may eventually be resorption of the underlying bones (autoamputation). Nail dystrophy and milia are marked, and scarring alopecia is common (Fig 4.29). Oral involvement is severe, with blisters, erosions, and scarring. Excessive caries are usual. Gastrointestinal and renal complications are common.^82,83 There is often conjunctival involvement with keratitis and scarring, and lesions of the mucous membranes result in difficulty in opening the mouth, dysphagia, and esophageal stricture formation, with some infants eventually succumbing to terminal respiratory infections (Fig. 4.30).⁸⁴ Anal and genitourinary involvement may also be present. Squamous cell carcinoma is a common complication of the cutaneous scarring (occurring in 39.6% of cases) and is a significant cause of mortality (Figs 4.31–4.33).^85,86 Tumors are frequently multiple, have an aggressive behavior, and may be associated with extensive metastatic spread. Melanoma much less commonly develops. This variant of EB has a high mortality: 38.7%.⁷

Fig. 4.24 Recessive dystrophic EB (Hallopeau-Siemens): extensive blistering present at birth. The disease process has involved the nails and those of the first two toes are absent.

By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 4.25 Recessive dystrophic EB (Hallopeau-Siemens): note the scarring and extensive erosions.

By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.26 Recessive dystrophic EB (Hallopeau-Siemens): weblike folds enveloping the toes have resulted in a clublike appearance.

By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 4.27 (A, B) Recessive dystrophic EB (Hallopeau-Siemens): in addition to the gross mitten deformity, there is very severe scarring and scaling.

(A) By courtesy of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas’ Hospital, London; (B) by courtesy of the Institute of Dermatology, London, UK.

Fig. 4.28 Recessive dystrophic EB (Hallopeau-Siemens): there is gross deformity of the knees.

By courtesy of J. McGrath, MD, Institute of Dermatology, London, UK.

Fig. 4.29 Recessive dystrophic EB (Hallopeau-Siemens): note the conspicuous milia.

By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.30 Recessive dystrophic EB: extensive esophageal involvement with complete separation of the mucosa has resulted in this dramatic, but fortunately very rare, manifestation.

By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 4.31 Recessive dystrophic EB (Hallopeau-Siemens): in this patient numerous large keratoses are evident. Many of these progress to squamous cell carcinoma. Courtesy of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas’ Hospital, London, UK.

Fig. 4.32 Recessive dystrophic EB (Hallopeau-Siemens): in addition to severe scarring accompanied by autoamputation of the fingertips, there is a large ulcerated squamous cell carcinoma.

Courtesy of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas’ Hospital, London, UK.

Fig. 4.33 Recessive dystrophic EB (Hallopeau-Siemens): in this patient there is a massive squamous carcinoma, which has destroyed much of the knee.

Courtesy of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas’ Hospital, London, UK.

Recessive dystrophic EB, generalized other

This type is often referred to as non-Hallopeau-Siemens type. In contrast to the severe generalized form, anemia and mental retardation are less common and dental caries are not increased. In this variant the features are similar to the Hallopeau-Siemens variant except that the extracutaneous lesions and complications (e.g., anemia, mental retardation, and dental caries) are less severe and the risk of developing cutaneous squamous cell carcinoma is diminished (14.3%).^4,8 The mortality for this variant of EB is 10.0%.⁸⁷ Genotypic differences in mutational types and sites in the gene encoding type VII collagen likely underlie differences in the phenotypic expression of this disease.⁸⁸