EB Simplex

The most common forms of EB simplex (EBS) are transmitted in an autosomal dominant manner. There are two main subgroups of EBS, suprabasal and basal, which differ in the ultrastructural level of the intraepidermal blistering (see Table 32.1 ). The vast majority of EBS cases are in the basal group, most often resulting from a dominant-negative mutation (see Ch. 54 ) within the keratin 5 ( KRT5 ) or 14 ( KRT14 ) genes, expression of which is primarily within the basal layer of the epidermis . The clinical severity and other phenotypic features of EBS are closely associated with the genotype. For example, mutations in the helix initiation and termination motifs of KRT5 and KRT14 (see Fig. 56.5 ) lead to the generalized severe subtype of EBS (EBS-gen/sev, previously known as EBS-Dowling–Meara), whereas the specific phenotype of EBS with mottled pigmentation almost always arises from a particular missense mutation in the V1 domain of KRT5. Dominant stabilizing mutations in the kelch-like protein 24 (KLHL24) ubiquitin ligase lead to EBS via increased ubiquitination and degradation of KRT14 . An autosomal recessive form of EBS due to mutations in the gene encoding plectin is associated with muscular dystrophy, which is not surprising considering that plectin is expressed in skeletal muscle as well as in the hemidesmosomes of basilar keratinocytes. Other EBS patients with plectin or α ₆ β ₄ integrin deficiency present with pyloric atresia, while rare autosomal recessive variants of basal EBS caused by mutations in the bullous pemphigoid antigen 1 or exophilin 5 genes have also been reported. In addition, suprabasal forms of EBS result from mutations in the genes encoding transglutaminase 5 and the desmosomal proteins plakophilin-1, plakoglobin, and desmoplakin (see Table 32.1 and Fig. 56.8 ).

Junctional EB

Junctional EB (JEB) is almost always transmitted in an autosomal recessive manner (see Table 32.1 ). The generalized severe subtype of JEB (JEB-gen/sev, previously known as JEB-Herlitz) typically results from homozygous or compound heterozygous truncating mutations within a gene encoding one of the three subunits of laminin 332, a key component of the lamina lucida of the dermal–epidermal junction (see Ch. 28 ) . In laryngo-onycho-cutaneous syndrome, the underlying mutations affect only the a isoform of the laminin α3 subunit. The milder generalized intermediate form of JEB (JEB-gen/intermed, previously known as JEB-non-Herlitz and generalized atrophic benign EB) results from mutations within the genes for either a subunit of laminin 332 or type XVII collagen. JEB with pyloric atresia, which is more common than EBS with pyloric atresia, is also caused by mutations within either of the two genes that encode the subunits of α ₆ β ₄ integrin. A newly recognized form of JEB associated with respiratory and renal involvement results from mutations in the integrin α ₃ chain.

Dystrophic EB

Dystrophic EB (DEB) is transmitted in either an autosomal dominant or autosomal recessive manner and is caused by mutations in the type VII collagen gene. Dominant DEB (DDEB) results from dominant-negative mutations, typically a missense mutation that leads to substitution of another amino acid for a glycine within the triple-helical domain of this collagen. Although the resultant protein is structurally abnormal, immunohistochemical staining of the dermal–epidermal junction is usually indistinguishable from that of normal skin.

Recessive DEB (RDEB) is usually due to compound heterozygous mutations within the type VII collagen gene . Premature stop codons, which result in truncated proteins, are characteristic of the generalized severe subtype (RDEB-gen/sev, previously known as RDEB-Hallopeau–Siemens). Consistent with the severity of these mutations, anchoring fibrils are undetectable or extremely sparse and poorly formed in skin biopsy specimens, and immunohistochemical staining with antibodies against the major epitopes of the type VII collagen molecule is absent or barely detectable. Milder forms of generalized RDEB are associated with less severe biallelic mutations in the type VII collagen gene.

Recently, a single nucleotide polymorphism in the matrix metalloproteinase 1 gene promoter has been identified as a disease modifier in RDEB . It is likely that additional modifying genes account for some of the inter- and intra-familial phenotypic variability observed in this and other forms of EB. There is also evidence for secondary effects from loss of protein expression in EB. For example, loss of collagen VII in RDEB fibroblasts leads to alterations in dermal matrix proteins, metalloproteinases, and transforming growth factor β (TGF-β), which are thought to further influence keratinocyte adhesion and dermal–epidermal integrity .

Some patients with RDEB retain the amino terminal non-collagenous domain (NC1) of type VII collagen, and this specific fragment may contribute to an increased susceptibility to develop squamous cell carcinomas (SCCs) . In a Ras-driven model of tumorigenesis, RDEB keratinocytes that contained no type VII collagen did not form tumors in mice, whereas RDEB keratinocytes that produced the NC1 domain of type VII collagen were tumorigenic. Additional studies have pointed to the fibronectin-like sequences within NC1 as key to promoting tumor cell invasion. However, SCCs can also develop in RDEB patients who do not express the NC1 domain .

In a rare form of DEB referred to as bullous dermolysis of the newborn, inheritance is usually dominant and blistering is typically confined to the first 1–2 years of life . Clinical expression coincides with a time during which type VII collagen is present primarily within basilar keratinocytes in these patients’ skin, rather than along the dermal–epidermal junction (see Fig. 32.1D ). This suggests that there may be a temporary disruption in the transport of this protein from the keratinocyte cytoplasm to the underlying ECM.

Cutaneous Findings

All forms of inherited EB are characterized by mechanically fragile skin, erosions, and (with rare exceptions) macroscopic blisters ( Figs 32.2 & 32.3 ). Scarring is almost always atrophic and can occur in any subtype of EB ( Fig. 32.4 ), including localized EBS. However, scarring is most frequent in the subtypes that are characterized clinically by generalized disease activity and ultrastructurally by disruption of the basement membrane, particularly the lamina densa ( Fig. 32.5 ). Whereas scarring is estimated to occur in only 15% of patients with localized EBS, it is present in essentially every patient with RDEB . Other cutaneous findings that have similar variations in frequency across the major types and subtypes of EB include dystrophic or absent nails (see Fig. 32.4 ), milia, and scarring alopecia of the scalp.

Localized epidermolysis bullosa simplex.

A, B Bullae arising on the toes and plantar surfaces at sites of lateral or rotary traction. The majority of blisters occur in acral sites.

B, Courtesy, Julie V Schaffer, MD.

Generalized intermediate epidermolysis bullosa simplex.

Extensive blistering on the buttocks ( A ) and blistering in association with focal keratoderma on the soles ( B ) of a 2-year-old girl.

Courtesy, Julie V Schaffer, MD.

Dominant dystrophic epidermolysis bullosa.

A, B Erosions, scarring and milia on the fingers. Note the partial ( A ) to almost complete ( B ) loss of the nails. C A discrete area of scarring on the elbow with blisters, crusting and milia.

B, Courtesy, Julie V Schaffer, MD.

Frequency of selected cutaneous findings within each major subtype of inherited epidermolysis bullosa (EB).

Note the increasing frequency from localized EB simplex (EBS) to recessive dystrophic EB (RDEB). JEB, junctional EB; DDEB, dominant dystrophic EB.

Some cutaneous findings have diagnostic implications ( Fig. 32.6 ) . Reticulated hyperpigmented macules distinguish a rare subtype of EB simplex termed EBS with mottled pigmentation . Superficial peeling of the skin, often in the absence of overt blistering, is seen in EBS superficialis (EBSS) and acral peeling skin syndrome ( Fig. 32.7 ) . Grouped (“herpetiform”) blisters, often in an arcuate ( Fig. 32.8 ) or polycyclic array, are highly characteristic of EBS-gen/sev , which is also associated with the gradual development of a diffuse palmoplantar keratoderma ( Fig. 32.9 ). Migratory circinate erythema with vesiculation of the advancing edge has been described in patients with EBS caused by a frameshift mutation that leads to an elongated KRT5 protein. Excessive or exuberant granulation tissue, usually in a symmetric distribution involving the periorificial areas, skin folds, upper back, nape of the neck, and periungual areas, is typical of JEB-gen/sev ( Fig. 32.10 ). Extremely pruritic papules coalescing in a linear arrangement on the lower extremities are characteristic of DEB pruriginosa ( Fig. 32.11 ).

Helpful cutaneous findings in patients with epidermolysis bullosa (EB).

DEB, dystrophic EB; EBS, EB simplex; JEB, junctional EB.

Acral peeling skin syndrome.

Superficial peeling of the skin on the ankle and dorsal aspect of the foot.

Courtesy, E Sprecher, MD, PhD.

Generalized severe epidermolysis bullosa simplex.

Clustered vesicles in an arcuate array on the thigh of this child.

Courtesy, Julie V Schaffer, MD.

Generalized severe epidermolysis bullosa simplex.

Diffuse palmar keratoderma in an adult.

Generalized severe junctional epidermolysis bullosa.

A Blisters on the elbow and large areas of denuded skin; note the bright red color in the axilla and groin. B Blisters and large erosions on the abdomen of an infant.

B, Courtesy, Julie V Schaffer, MD.

Dystrophic epidermolysis bullosa, pruriginosa.

Prurigo-like papulonodules coalescing into linear plaques on the shin as a consequence of chronic scratching.

Distribution of skin disease activity is also useful in the subclassification of EB , although the pattern of involvement tends to be less distinctive in infants than in adults. Patients with the “ inversa ” subtypes of JEB and RDEB experience severe disease activity primarily in intertriginous areas such as the axillae and inguinal creases. In contrast, patients with localized JEB have involvement mainly in acral sites, and those with pretibial DEB have lesions almost exclusively on the shins. RDEB centripetalis is a rare subtype that initially features acral blistering, followed by slow progression of disease activity toward the trunk over the years.

Extracutaneous Findings

The molecular defects that affect the skin in patients with EB may also lead to manifestations in other tissues with an epithelial lining or surface , including the eye, oral cavity, and gastrointestinal, genitourinary, and respiratory tracts. Major extracutaneous complications of EB are summarized in Table 32.2 . Although exceptions exist, extracutaneous involvement occurs most frequently in RDEB and JEB, and it can result in blisters, erosions, ulcers, and scarring. Rare subtypes of JEB and EBS present at birth with pyloric atresia as well as skin fragility and blistering . In other forms of EB, extracutaneous disease may become apparent as early as the first few months of life. Repeated blistering of the external eye can result in neovascularization and blindness . Chronic involvement of the esophagus leads to scarring, stricture formation and, rarely, even complete obstruction . Involvement of the small intestine presents with chronic malabsorption, whereas disease activity within the large intestine tends to produce constipation and anal fissures or strictures. Recurrent genitourinary tract blistering may result in urethral or ureterovesical strictures; if persistent, the latter may eventuate in ureteric reflux and hydronephrosis. Tracheolaryngeal blistering and associated soft tissue edema, seen most often in infants and young children with JEB-gen/sev , may lead to potentially fatal acute airway obstruction . JEB with respiratory and renal involvement is a rare subtype associated with severe interstitial lung disease.

Dental enamel hypoplasia, which occurs in all forms of JEB , is associated with pitting of the surfaces of primary and permanent teeth. If untreated, affected individuals lose teeth during childhood due to excessive caries . Severe caries and resultant tooth loss also occur in RDEB-gen/sev , likely resulting from impaired clearance of food from the mouth and poor dental hygiene in the setting of intraoral injury and scarring, ankyloglossia, and microstomia.

Pseudosyndactyly (“mitten” deformities) of the hands and feet primarily affects patients with RDEB, especially RDEB-gen/sev , although it occasionally occurs to a lesser degree in DDEB and JEB ( Fig. 32.12 ). Initially presenting as proximal web formation between adjacent digits, the digits may eventually become totally fused and encased by scar tissue. Lack of mobility leads to bone resorption and muscular atrophy, and hand function is severely compromised.

Generalized severe recessive dystrophic epidermolysis bullosa.

A Early proximal interdigital web formation together with atrophic scarring and loss of nails in a 5-year-old girl. B Partial “mitten” deformities of the hands in an older child.

A, Courtesy, Julie V Schaffer, MD.

Osteoporosis, detectable by dual-emission X-ray absorptiometry (DEXA) scanning, is common in RDEB-gen/sev and JEB-gen/sev . Radiographs may demonstrate vertebral crush fractures in severe cases. EBS due to plectin deficiency is associated with mild to severe muscular dystrophy. Although the muscle disease presents during infancy in some patients, weakness often develops insidiously during later childhood or even early adulthood in those who are less severely affected.

Chronic renal failure occasionally develops in patients with severe forms of EB, most notably RDEB-gen/sev , which is associated with a ~10% risk of death from renal failure by age 35 years . Renal disease may result from untreated outflow obstruction, glomerulonephritis, secondary systemic amyloidosis or IgA nephropathy. Nephrotic syndrome associated with altered expression of laminin isoforms in renal basement membranes has been reported in an infant with JEB-gen/sev and it occurs congenitally as a result of integrin α ₃ mutations in JEB with respiratory and renal involvement. A small subset of patients with severe forms of EB, especially RDEB-gen/sev , develop potentially fatal dilated cardiomyopathy . Although as yet unproven, selenium or carnitine deficiency may be a contributing factor.

Although it was a common occurrence several decades ago, potentially lethal bacterial sepsis is now relatively rare in inherited EB , presumably due to improved wound care and the availability and judicious use of broad-spectrum antibiotics. When sepsis does occur in EB, it tends to affect infants with generalized severe disease . In contrast, failure to thrive is still common among infants with JEB-gen/sev and may lead to death.

Cutaneous Malignancies

A major complication, usually of RDEB, is the development of multiple cutaneous SCCs . These tumors most often arise in chronic non-healing wounds or hyperkeratotic lesions ( Fig. 32.13 ). Histologically, they are usually well differentiated. However, the borders of the lesions are often indistinct and they are difficult to completely excise, with a tendency to recur locally. In addition, SCCs in EB patients frequently metastasize and are strikingly unresponsive to chemotherapy or radiotherapy. Indeed, they represent the leading cause of death in EB at or after mid-adolescence, with death from an SCC of cutaneous origin occurring in most patients within 5 years of the diagnosis of their first SCC . These tumors occur primarily in RDEB, especially RDEB-gen/sev, although SCCs can also develop in adults with generalized JEB. The cumulative risk of at least one SCC in patients with RDEB-gen/sev is 7.5% by age 20 years but rises to 68%, 80%, and 90% by ages 35, 45, and 55 years, respectively . In contrast, the risk of SCC in other forms of RDEB is <25% by age 45 years .

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