Bullous disorders of childhood

Classical epidermolysis bullosa simplex

EBS most commonly results from mutations in the genes encoding keratin 5 and keratin 14 (the keratins expressed in basal cells). Keratins are the most abundant proteins of epidermal keratinocytes, and keratin pairs are critical for the filamentous network that provides integrity to epidermal cells. When a point mutation occurs in one of the keratin alleles, resulting in a change in one amino acid, the abnormal keratin protein is still able to form filaments, but these filaments are abnormal. The abnormal filaments do not provide adequate structural integrity to the cell, and as a result, the cell lyses. Cytolysis of epidermal basal cells is the essential histologic feature of all forms of EBS resulting from keratin gene mutations. Electron microscopic examination shows cleavage through the basal layer (above the periodic acid–Schiff-positive basement membrane of the epidermis). In the severe generalized form, clumping of tonofilaments and displacement of nuclei are seen ultrastructurally. The risk of cell lysis and the trauma required to elicit the blistering depend on the site of the mutation and how critical that gene region is for resultant keratin function. The sites of mutations in generalized severe EB simplex are those most critical for keratin function (end-terminal rod domains), whereas the sites mutated in the localized type are less critical.

Severe EBS (formerly Dowling–Meara) is the most severe form of EBS from keratin gene mutations ( Table 13.2 ). During the newborn period, the generalized blisters tend to be large and may be difficult to distinguish from those of the severe dystrophic or junctional forms of EB despite the relatively good overall prognosis of babies with this form ( Fig. 13.3 ). Many young infants also show a significant inflammatory reaction in association with blistering and the formation of transient milia at sites of healed blisters, a finding usually characteristic of the dystrophic forms. The characteristic small, clustered (herpetiform) blisters may be seen in neonates, especially on the proximal extremities or trunk, but are more commonly noted during infancy and later childhood ( Fig. 13.4 ). Blistering tends to decrease during later childhood and adulthood, and hyperkeratosis of the palms and soles may develop by 6 or 7 years of age, especially in those younger children with significant palmoplantar blistering ( Fig. 13.5 ). During the neonatal period and early infancy, the extensive blistering may prove life-threatening. After this period, however, the blistering is rarely a threat to life. As with all types of EB, pigmented nevi may occur (EB nevi) ( Fig. 13.6 ). EB nevi are dark, irregular hyperpigmented patches that may be worrisome dermoscopically but show benign nevi or increased basal pigment deposition histologically ^, and typically clear spontaneously during the subsequent months to years. Nail involvement with sloughing, hemorrhage, and transient dystrophy is common in the generalized severe form ( Fig. 13.7 ). Oral and esophageal mucosal blistering may occur and cause problems with feeding and obtaining adequate nutrition, especially with the markedly increased caloric needs of more severely affected infants and younger children. Ocular mucosal blistering is less common, but natal teeth have been described.

Intermediate EBS (formerly Koebner EBS) is characterized by generalized blistering of skin, most notable at sites of friction (see Table 13.2 ). Extensive blistering in the neonatal period and early infancy increases the risk of sepsis and may be life-threatening. In general the tendency toward blistering tends to improve with advancing age, particularly by the teenage years. Hyperhidrosis is common, and mild to moderate hyperkeratosis of the soles is often present. Although erosions of the mucous membranes may be seen in the newborn as a result of vigorous sucking, mucosal involvement is generally mild and the nails are rarely affected, in contrast to the generalized severe form. Involvement of the conjunctiva and cornea has rarely been described.

Localized EBS (formerly Weber–Cockayne EBS) is the most common clinical variant (see Table 13.2 ). A relatively high threshold of frictional trauma is required to induce blister formation. Bullae are usually confined to the hands and feet (primarily the palms and soles; Fig. 13.8 ); they are often first seen in infants but may not appear until adolescence or early adulthood. The bullae are usually associated with trauma, occur more readily in hot weather with sweating of the feet, and do not tend to be seriously debilitating, although activities that involve trauma to the feet are often restricted. Associated hyperhidrosis is common and may exacerbate blistering. Keratoderma of the palms and soles occurs with advancing age, especially in children with more plantar-area trauma ( Fig. 13.9 ), but tends to be milder than with other keratinopathies, such as epidermolytic ichthyosis from KRT1 mutations or pachyonychia congenita. Lesions heal rapidly without scarring, nail involvement rarely occurs, and the mucous membranes do not tend to be involved. In young children, blisters may develop on the knees from the frictional trauma of crawling. In adolescents and young adults, blisters often occur on the feet after long hikes or dancing or on the hands after a game of tennis or golf.

EBS with mottled pigmentation is characterized by a mottled, reticulated pigmentation ( Fig. 13.10 ), particularly of the trunk and neck, in association with mild acral blistering (see Table 13.2 ). Patients often show small verrucous papules of the hands and feet and palmoplantar keratoderma. The mutations that lead to EBS with mottled pigmentation tend to be at the head region of KRT5 or KRT14 (most often a mutation that changes the 25th amino acid of keratin 5), ^, suggesting that this site on the keratin protein is vital for the transfer of pigment from melanocytes to keratinocytes. Migratory circinate EBS (see Table 13.1 ) is characterized by small blisters on the hands, feet, and legs with migratory circinate erythema and often postinflammatory hyperpigmentation. Mucosal and nail involvement have not been described. The migratory circinate form has been linked to specific frameshift mutations in the V2 tail region of KRT5 .

Autosomal recessive EBS from mutations in KRT5 / KRT14 can present with localized to generalized blistering. It can result from biallelic mutations in KRT5 or KRT14 , or can be digenic, with a combination of a mutation each in KRT5 and KRT14; in the latter, parents may be mildly affected or have normal skin.

Autosomal dominant EBS can also occur from mutations in KLHL24 . Blistering tends to be mild but is often present at birth and results in skin atrophy and scarring ( Fig. 13. 11 ). Distinguishing features include dyspigmentation, dystrophic nails, sparse hair (especially after the first decade), variable oral involvement, follicular atrophoderma, dilated cardiomyopathy, ^, and neurologic abnormalities, including seizures. Mutations in KLHL24, encoding Kelch-like protein 24, affect the initiation codon region and result in an increase in ubiquitination and thus accelerated degradation of keratin. ^, The increase in keratin 15, which can also form heterodimers with keratin 5, is thought to be compensatory.

Mutations in the gene encoding plectin ( PLEC ) can lead to either autosomal dominant or recessive EBS. ^, The dominant form (called EBS-Ogna in the past) predominantly has acral blistering, although more generalized blistering has been described. Affected individuals characteristically bruise easily and may show onychogryphosis. Autosomal recessive forms are usually associated with muscular dystrophy or pyloric atresia. EBS with muscular dystrophy presents in the neonatal or infantile period with generalized blisters, but the onset of muscular dystrophy varies from infancy to adulthood. Patients may show ptosis, granulation tissue with stenosis of the respiratory tract, and focal keratoderma. The mutations of EBS with muscular dystrophy cluster in exon 31, which is spliced out in one of the two isoforms of plectin, explaining the much milder phenotype of EBS with muscular dystrophy. EBS with pyloric atresia presents with the same widespread congenital absence of skin (especially on the extremities), generalized blistering, and pyloric atresia as in JEB with pyloric atresia (from variants in genes encoding integrin α6 or integrin β4, see later). Malformed pinnae and nasal alae, joint contractures, and cryptorchidism are other shared features. Plectin interacts with α6β4 integrin, providing a rationale for similar clinical manifestations.

Autosomal recessive EBS (EBS-AR BP230) may result from mutations in DST-e (dystonin-e), the epidermal isoform of bullous pemphigoid (BP) antigen (BPAG1e or BP230). ^, Affected individuals experience blistering and erosions beginning in infancy, usually localized to the ankles and feet; however, an intermediate-severity form of EBS associated with prurigo papules has been associated with DST mutations.

Autosomal recessive EBS (EBS-AR exophilin 5) may also occur due to mutations in EXPH5, encoding exophilin-5 (or SLAC2b), which is a protein involved in vesicle transport. Small, localized erosions and bleeding primary affect sites of trauma, primarily the lower back, knees, and ankles. Mottled pigmentation has been associated. Exophilin-5 co-localizes with integrin β4 at the keratinocyte periphery and affects its adhesion to the laminin-332 matrix. Ultrastructural studies show typical perinuclear cytoplasmic vesicles in addition to keratin filament clumping and acantholysis (which is occasionally seen in EBS related to keratin gene mutations). ^,

EBS localized with nephropathy is associated with biallelic mutations in CD151, which encodes a tetraspanin expressed in keratinocytes at the dermal–epidermal junction. Cutaneous features are pretibial blistering (sometimes more widespread), poikiloderma, ^, and acrogeria. Tetraspanin 24 (formerly called tetraspanin 151 ) is a component of basement membranes that forms complexes with integrins, including α3β1 and α6β4 in skin. Patients also have oral erosions, nail dystrophy, early-onset alopecia and loss of teeth, nasolacrimal duct stenosis, esophageal webbing and strictures, and corneal vascularization. An important feature is protein-wasting nephropathy, given the important role of tetraspanin 24 in glomerular function and renal tubules.

Erosive, peeling, and hyperkeratotic disorders with skin fragility

Biallelic mutations in DSP, PKP1, and JUP, all encoding desmosomal proteins, can lead to autosomal recessive erosive disorders with skin fragility associated with suprabasal cleavage and acantholysis in histologic sections ( Table 13.3 ). Mutations in the C-terminal domain of DSP lead to generalized denudement at birth with absence of hair and nails (formerly called the lethal acantholytic form of EB , or LAEB ). ^, Frank blisters are not seen, but the skin peels in sheets ( Fig. 13.12 ). Mucosal sloughing is severe, and affected neonates may be born with teeth. All babies to date have died in the neonatal period. Cardiomyopathy is usually associated. Mutations have been described in the C-terminal domain of DSP . Less deleterious mutations in DSP also cause skin fragility and woolly hair syndrome (see Chapter 7 ), characterized by superficial erosions and crusting with woolly hair, palmoplantar keratoderma, and cardiomyopathy.

Mutations in JUP, encoding plakoglobin, manifest at birth as generalized erythroderma with superficial peeling and erosions. Patients have alopecia, dystrophic nails, and recurrent infections and generally die in the neonatal period, but without cardiac issues. ^, As with other mutations in desmosomal components, a milder form allows survival but the development of generalized erosions, sparse woolly hair, and focal keratoderma.

Plakophilin deficiency (skin fragility and ectodermal dysplasia syndrome) results from mutations in PKP1, the gene encoding plakophilin-1. Affected patients show generalized erythroderma at birth with blistering. The soles are often most disabling, with palmoplantar keratoderma and painful fissures. Superficial erosions and crusting are prominent in the perioral area, and tongue fissures have been described. The hair tends to be short, sparse, and woolly, and the nails are thickened and dystrophic. Affected individuals show variable hypohidrosis, blepharitis, and growth retardation. Plakophilin-1 is a structural component of the desmosomes that allows cell–cell adhesion; biopsies of affected skin show acanthosis, acantholysis, widening of the space between keratinocytes, and few poorly formed desmosomes.

Several disorders result in peeling of skin without erosion (see Table 13.3 ). An acral peeling skin syndrome results from mutations in TGM5, the gene encoding transglutaminase 5. The subcorneal cleavage can be confused with localized EB on the hands and feet. Several additional disorders present with peeling skin in an acral or generalized distribution; these result from biallelic pathogenic variants in genes encoding calpastatin, cathepsin B, cystatic A, corneodesmosin, desmoglein 1 (SAM syndrome), filaggrin 2, LEKTI (Netherton syndrome), and serine protease inhibitor 8 (serpin B8) (see Chapter 5 ). Inherited keratinopathies of suprabasal keratinocytes can also present with blisters, but in association with predominant hyperkeratosis. These include the epidermolytic ichthyoses (caused by mutations in KRT1, KRT2, and KRT10) (see Chapter 5 ) and pachyonychia congenita (caused by mutations in KRT6A, KRT 6B, KRT6C, KRT16, and KRT17) (see Chapter 7 ).

Dystrophic epidermolysis bullosa

The scarring (dystrophic) types of EB are predominantly divided into dominant dystrophic epidermolysis bullosa (DDEB) and RDEB forms, and their various subtypes are based on severity, distribution, and characteristics ( Tables 13.6 and 13.7 ). All forms of DEB affect anchoring fibrils, critical elements for epidermal–dermal cohesion, and most result from mutations in type VII collagen.

The one exception to collagen VII as the underlying mutated gene is a syndromic dystrophic blistering disease is connective tissue disorder with skin fragility , resulting from biallelic variants in PLOD3, encoding lysyl hydroxylase 3 (LH3), a key enzyme in the posttranslational modification of type VII collagen. ^, LH3 glycosylates the hydroxylysine group of collagen VII and is reduced in the skin of all RDEB patients. Patients with PLOD3 mutations present with trauma-induced blistering (extremities, ears) beginning during infancy, delayed wound healing, and dystrophic nails, as well as poor growth, developmental delay, several eye abnormalities, dysmorphic facies, connective tissue abnormalities (prominent knees, scoliosis, osteopenia, flexion contractures of the elbows and carpometacarpal joints, talipes equinovarus, and webbing at fold areas), and variable deafness and dilatation of blood vessels. The level of blistering is below the lamina densa, and the extent of reduced and abnormal-appearing anchoring fibrils is variable. The early blistering distinguishes this syndromic form of EB from connective tissue disorders, particularly the spondylocheirodysplastic form of Ehlers–Danlos syndrome, which results from mutations in PLOD1 (see Chapter 6 ).

In general, the dominant forms are considerably less severe; affected individuals are generally healthy, are of normal stature, and show limited blistering of the skin. The severe generalized form of RDEB, conversely, is severe and incapacitating. Functional deformities of the hands and feet result from extensive scarring, growth and development are retarded, and profound anemia and hypoalbuminemia are standard.

Dominant dystrophic epidermolysis bullosa

Dominant dystrophic epidermolysis bullosa (DDEB) usually presents at birth or shortly thereafter. There is great phenotypic variability, even within families. Some cases present as isolated milia, nail changes (DDEB, localized, nails only), blistering limited to the acral areas of the hands and feet, or prurigo papules. In some individuals with mild disease, the diagnosis is not recognized until manifestations appear in adulthood. Interestingly, a large deletion of approximately 40% of COL7A1 has led to a mild form of DDEB, with the expression of a shorter collagen VII protein that could still assemble and function.

Nevertheless, the typical features are blisters, with resultant scars and milia, primarily involving the extensor areas of the extremities and the dorsal surface of the hands ( Figs. 13.18 and 13.19 ). Nail thickening, dystrophy, or complete nail destruction are seen in 80% of cases ( Fig. 13.20 ). Although mucous membrane lesions appear in 20% of cases, they tend to be mild and not problematic. The teeth and hair are generally not affected, and physical development is normal.

DEB pruriginosa (DEB-Pr) is a poorly understood form of DEB (usually dominant) with the onset of severe associated pruritus and prurigo-like, scarred vesicles and papules primarily of the pretibial areas ( Fig. 13.21 ). Onset is often delayed until adolescence or adulthood in patients with typical features of DDEB during childhood.

The self-improving form (formerly called bullous dermolysis of the newborn ) shows skin blistering, often extensive, at birth or in early infancy ( Fig. 13.22 ). However, blistering dramatically improves during the first months to 2 years of life, and affected individuals usually have only mild residual atrophy, scarring, and nail dystrophy thereafter. The disorder results from certain mutations in COL7A1 that lead to the milder phenotype and can be inherited in a dominant or recessive manner. Characteristically, epidermal cells show intracytoplasmic retention (rather than secretion) of type VII collagen.

Recessive dystrophic epidermolysis bullosa

Children with severe RDEB (formerly called the Hallopeau–Siemens type ) have a severe, life-altering bullous disease characterized by widespread dystrophic scarring and deformity and by severe involvement of mucous membranes. RDEB may manifest as a less severe form (intermediate RDEB), with less severe blistering of the skin and mucosae that may be mistaken for DDEB ( Fig. 13.23 ). Individuals with this milder form often begin to have increasing problems with mucosae, especially esophageal function, in adolescence. Blistering in RDEB inversa tends to be localized to the intertriginous axial, lumbosacral, and acral sites, in addition to extensive mucosal involvement, including esophageal strictures and external auditory canal stenosis.

Although any area of the skin may be involved in infants with generalized severe RDEB, the most commonly affected areas are the hands, feet, buttocks, scapulae, face, occiput, elbows, and knees. In older children the hands, feet, knees, elbows, and posterior neck and/or upper mid-back ( Fig. 13.24 ) are most commonly involved. Bullae may be hemorrhagic, and large areas, especially on the lower extremities, may be completely devoid of skin. When a blister ruptures or its roof peels off, a raw, painful surface is evident. The Nikolsky sign (production or enlargement of a blister by slight pressure or the production of a moist abrasion by slight pressure on the skin) is often positive. Fluid contained in bullae, although at first sterile, may become secondarily infected ( Fig. 13.25 ), which can lead to sepsis; Staphylococcus aureus and Pseudomonas aeruginosa are the most common organisms.

Bullae are often followed by atrophic scars and varying degrees of hyperpigmentation or hypopigmentation. Milia overlying the scars are characteristic. EB nevi are common (see earlier). The hands and lower aspects of the legs are particularly susceptible to severe blistering and scarring. The fingers and toes may become fused, with resultant pseudosyndactyly in which the digits become bound together by a glove-like epidermal sac, with resulting claw-like clubbing or mitten-like deformities ( Fig. 13.26 ). The fingers and toes become immobile (usually during the first years of life), and the wrists, elbows, knees, and ankles may become fixed in a flexed position from contractures, leading to immobility and often confinement to a wheelchair.

Oral mucosal involvement occurs soon after birth ( Fig. 13.27 ), leading to dysphagia and limiting the ability to suck well. Erosions of the esophagus may at times result in segmental stenosis (most often in the upper third) with consequent difficulty in swallowing. Gastroesophageal reflux disease often occurs, especially presenting as effortless vomiting. Constipation is common and may be related to anal fissuring, inadequate dietary fiber, and administration of iron. Affected children are reluctant to eat and often fail to thrive, given their increased nutritional needs due to loss of protein and other nutrients through wounds. As the child grows older, there is a tendency for the disease to become less severe, but the affected individual also soon learns to avoid hot drinks, rough foods, and large particles that might produce blistering of the mouth, pharynx, or esophagus. Typically, patients show microstomia due to intraoral scarring and a frenulum that is bound down. The eyes may develop blisters with associated ocular inflammation and later corneal scarring, potentially leading to visual impairment. Hoarseness, aphonia, and even laryngeal stenosis may result from laryngeal blistering and scarring. Bone mineralization is low in patients with EB, particularly those with RDEB, probably due to a combination of insufficient nutrition, reduced physical activity, and chronic inflammation. ^,

The teeth in RDEB are particularly susceptible to early and commonly severe caries. The progressive intraoral scarring leads to microstomia and decreased salivation. ^, Even routine dental care may cause the eruption of bullae and erosions on the lips, gingivae, and oral mucosa. The nails may show severe dystrophy or complete absence of nails. Scalp and body hair may be sparse, and there may be patches of cicatricial alopecia.

In patients with the severe generalized form of RDEB, death may occur during infancy or childhood as a result of septicemia, pneumonia, or renal failure. Patients with RDEB (and rarely DDEB) have an increased risk of glomerulonephritis, renal amyloidosis, and immunoglobulin (Ig) A nephropathy. ^, The tremendous loss of fluid, blood, and protein through the skin coupled with malnutrition can lead to hypoalbuminemia and anemia. Dilated cardiomyopathy is an uncommon complication (4.5% by 20 years of age) but may be fatal, especially in the presence of concurrent chronic renal failure. The cause of the cardiomyopathy may be multifactorial, including from transfusion-associated iron overload, viral myocarditis, and deficiency of selenium and carnitine. Other complications of RDEB include erosions and scarring of the anal area (often resulting in severe discomfort, chronic constipation, or soiling), urethral stenosis, urinary retention, hypertrophy of the bladder, and occasionally hydronephrosis. ^,

Patients with RDEB (and, to a much lesser extent, JEB and DDEB) show a progressively increasing risk of developing cutaneous SCCs with advancing age; in a recently described Australian cohort, the earliest age of development was 16 years with a cumulative risk of developing SCC of 76% by 35 years of age. ^, In another study the accumulative risk of SCC in RDEB was 13% by 20 years of age. The SCCs tend to occur in heavily ulcerated and scarred areas of skin. Lesions are predominantly over joints and on the distal extremities and present as nodular lesions or nonhealing ulcers. ^, Suspicious masses should be biopsied to distinguish SCCs from benign lesions such as verruciform xanthoma. ^, SCCs rarely appear on the tongue or esophagus. Cutaneous carcinomas tend to be locally aggressive, often requiring amputation, and almost 70% metastasize, often leading to death within 4 to 5 years after SCC development. The genetic mutations found in RDEB SCCs are similar to those alterations found in ultraviolet light–related cutaneous SCCs. Melanoma may arise in children with RDEB, whereas the risk of developing basal cell carcinomas seems to be increased in adults with generalized severe EBS.

Although death during childhood is most common with JEB (median age 4 to 6 months) due to sepsis, failure to thrive, and respiratory failure, children with RDEB generally survive the neonatal and infantile periods but succumb to infection later during childhood or to aggressive cutaneous carcinomas during adulthood.

Treatment of epidermolysis bullosa

EB is a group of disorders in which multidisciplinary care provides the best option for the patient, especially in patients with more severe disease. Currently, treatment of EB is largely palliative, with protection from friction or overheating, avoidance of abrasion and constriction, control of secondary infection, nutritional supplementation, and pain control.

As in any inherited disorder, it is the responsibility of the physician to inform parents of the risks of transmitting genetic abnormalities. When the condition is determined by a dominant gene (as in DDEB) ^, and a parent is affected, the risk of the disorder in siblings is 50%. In a family in which a child manifests abnormalities because of a recessive gene (as in RDEB), parents risk a 25% possibility with each pregnancy of the disorder occurring in future offspring. Appropriate genetic counseling, however, depends on accurate diagnosis. For example, some recessive forms of EB may result from uniparental isodisomy (i.e., inheriting two copies of a mutated gene from a single parent), in which case the chances of having another affected child is <1%. ^, Similarly, a dominant disorder in which the genetic mutation occurs in the early postzygotic period has no greater chance of occurring in a sibling than in the general population; however, if one of the parents has germline mosaicism, the risk is higher. Because the clinical course of many forms of EB is variable, especially during the neonatal and infantile periods, it is recommended that patients be carefully evaluated as early as possible with genotyping, if accessible, although immunofluorescent mapping can provide important information as well. Prenatal diagnosis of all forms of EB is now available using molecular techniques, but is easiest if the gene defect is known in that family. Preimplantation diagnosis has been performed and is an option that utilizes in vitro fertilization to ensure a normal fetus without the risk of abortion. ^,

The psychosocial effects of EB, especially the more severe forms, on the affected individual and family are among the most dramatic of any skin disease. Affected children are concerned about having itchy skin, being in pain, having difficulty with participation, failing to understand others, and feeling different. Parents of affected children worry about the child being different, the child suffering pain, feeling uncertain about the future, restrictions on employment and leisure, problems with organizing care, being constantly on duty, family problems, the ignorance and lack of skills of alternative care providers, and resistance by the child to care. These problems should be discussed and psychological support for patients and their families offered as part of optimal care. In addition, the economic impact on the family of a child with EB can be devastating, not merely from the cost of medication, dressings, and in-patient and outpatient medical care but also because of the tendency for one parent to stop working to care full-time for the child, leading to loss of income.

Practical measures to reduce blistering.

Because blisters result from mechanical injury, measures should be taken to relieve pressure and prevent unnecessary trauma. During hospitalization and procedures, care must be taken to educate the healthcare team about EB and the required adjustments in care to minimize skin and mucosal trauma. Clothing should be soft and worn inside out. Labels that may rub the skin should be removed. Velcro closures are less traumatizing than other traditional closures. Mittens can be worn to minimize self-induced trauma. A cool environment and lubrication of the skin to decrease surface friction are helpful in the reduction of blister formation. A water mattress and a soft fleece covering will also help limit friction and trauma. Applying nonstick dressings (such as Mepilex Lite) under electrocardiogram (ECG) leads and other adhesive surfaces prevents adhesive contact directly with the skin, and foam dressings can also be used as a cushion beneath blood pressure cuffs. Occupational therapy is important for maintaining function, particularly hand dexterity, and learning to prevent physical injury. Neoprene pads can be applied to protect areas of contact, and sheepskin liners can be made for seats and as modified grips. When blisters occur, extension may be prevented by aseptically puncturing the wound with a needle and releasing blister fluid. The roofs of blisters should be left intact whenever possible to protect the underlying skin.

Shoes should be soft and fit well; leather shoes with leather linings, ideally with external seams (e.g., moccasins), are usually recommended. During the summer, canvas shoes and jelly sandals are the best choices. Shoes should be large enough to accommodate dressings and minimize friction. Insoles can be made from cooling gel, sheepskin, or protective dressings.

In patients with EBS, keeping palms and soles cool and dry helps minimize blistering, especially during hot weather. Hyperhidrosis is often a concomitant feature, and measures to minimize the increased blistering associated with hyperhidrosis can be helpful. These include applying 20% aluminum chloride hexahydrate at night and gently drying the area with a cool hair dryer, wearing socks that absorb moisture, and sprinkling affected areas with absorbent powder such as Zeasorb. For extreme cases and in older patients with the localized form of EBS, injections of botulinum toxin A have been helpful. Silver-impregnated socks can also decrease infections and increase foot comfort.

Daily to every-other-day baths can help reduce crusting and discomfort. In one study of 16 children with primarily RDEB, saltwater baths (0.9% sodium chloride/normal saline, made by adding 1.5 pounds pool salt per 35-gallon tub) led to a significant reduction in pain and pain medication use in 91% and 66%, respectively. The bathtub can be lined with a thick towel, and affected babies can be lifted and moved on a soft pad. Topical application of protective petrolatum to eroded areas is helpful.

Protective dressings should be applied to eroded areas to promote healing and increase comfort. Use of dressings that do not adhere to wounds is critical to prevent further denudation when dressings are changed. In the neonatal period, petrolatum-impregnated gauze is commonly used with extra ointment applied to prevent adherence to the wound. The choice of dressings thereafter depends on access, wound exudation, and personal choice. Most use a nonadherent thin contact layer, topped with a padded secondary dressing. Tape and any significant pressure to skin must be avoided. Dressings can be held in place by a third layer of rolled gauze or loose self-adherent wraps with tape only applied to the dressing itself or by stockinette. DEBRA, the patient support organization, provides product names and recommendations for physicians and patients ( http://www.debra.org/careproducts#contact ). Among products often used in contact with the skin are nonadherent foams and hydrogels. Draining wounds need absorbent dressings, such as hydrofibers, calcium alginates, and foam products. Although nonadherent absorbent pads such as Telfa are inexpensive, they often stick to wounds with serous or purulent drainage, requiring vigorous soaking or greasing for removal without denudement. ^, A type I collagen dressing was shown to improve wound healing in RDEB in a small number of patients. Many advocate that dressings be carefully placed between the digits in children with RDEB to slow the development of pseudosyndactyly ( Fig. 13.29 ), although the ameliorative effect of this practice has not been tested.

Sterile precautions must be taken when changing dressings to reduce the risk of bacterial infection. Dressings with silver have helped patients with recurrent infections, but application of silver sulfadiazine has been associated with argyria. ^, Families need to weigh the antiinfective benefits with the risk of potentially high blood levels of silver. Bacteriostatic dressings with methylene blue and crystal-violet dyes (such as Hydrofera blue) and medical-grade honey are also available. It should be noted that children with EB have developed contact allergy to topically applied ointments or dressings, which may be difficult to diagnose given the challenge of doing patch testing.

Crusted or purulent areas should be cultured and treated based on the sensitivity of organisms. Infection may require administration of systemic antibiotics, but antibiotics should only be used for clinical infection because of the high risk of development of resistance and given the baseline reduction in microbial diversity in EB wounds. Choice of antibiotic (based on organism sensitivity), but not the decision to use an antibiotic, should be based on culture results, because most patients are colonized by S. aureus and/or P. aeruginosa in the absence of infection. Gentamicin soaks (480 mg/L saline) or acetic-acid soaks (diluted white vinegar) have been used to decrease the overgrowth of Pseudomonas and staphylococcal organisms. The risk of sepsis with cutaneous infection is high in neonates and infants, and patients should be monitored carefully.

Topical and systemic steroids are generally not useful for patients with EB and should be avoided in view of their increased risk of systemic absorption and promotion of side effects, including increased risk of infection. However, short courses of low- to moderate-strength topical steroids are sometimes useful for pruritus. The severely pruritic prurigo lesions of EB pruriginosa are traditionally managed by application of potent steroids, often under occlusion, but oral thalidomide ^, and cyclosporine have also been used. In addition, a potent topical steroid is the treatment of choice for localized areas of exuberant granulation tissue in JEB (for example, periungual). In two children who were unresponsive to potent topical steroids, topical timolol 0.5% ophthalmic drops applied twice daily to wounds led to full or almost complete healing in the wounds.

Pain control is an important component of EB care, especially in affected infants. Changing of dressings at blistered sites is excruciatingly painful for patients, yet must be performed from a few times weekly to up to twice daily, depending on the extent of drainage and the presence of infection. Evidence-based guidelines from DEBRA International for pain care were published in 2014. Among the stronger recommendations are that anxiolytics and analgesics (nonsteroidal antiinflammatory drugs [NSAIDs] and acetaminophen) be used for procedural pain and fear. Tramadol and other opioids are also used, but the common side effects of opioids—constipation and pruritus—are significant baseline problems in EB. Methadone should only be used under guidance from a pain specialist, given its risk of QT interval prolongation and dosing challenges. For older children, acetaminophen with codeine, oral midazolam, or morphine have been used before dressing changes and baths to improve tolerance. Because the pain has a burning quality that resembles neuropathic pain, gabapentin is often used. Topical anesthetics can be applied before venipuncture and other procedures to reduce local discomfort. Medications should be coupled with cognitive behavioral techniques, particularly distraction and breathing techniques, relaxation training, and biofeedback. Many patients claim benefit in healing and discomfort from the use of cannabidiol (CBD), especially topical CBD oil, but to date no studies have been done, and over-the-counter CBD is not regulated to assure safety and verify the stated formulation.

Overall, 85% of patients with EB complain of pruritus, which can be more problematic on a 5-point Likert scale than pain. The itch is less problematic with EBS than with the more severe JEB and DEB types and can interfere with sleep. Exacerbants are healing wounds, a hot environment, infection, high humidity, and stress. Antihistamines and topical creams and ointments are of limited value, ^, but short-term courses of mid-potency topical steroids and, as second-line agents, antidepressants (such as mirtazapine) and low-dose gabapentin or pregabalin can be considered. Serlopitant, a neurokinin-1 inhibitor, is currently being tested in EB as an antipruritic.

Nutritional supplementation is critical for patients with the more severe forms of EB to prevent failure to thrive, which has been linked to mortality in 20.5% of patients with generalized severe JEB by 2 years of age. The loss of protein, iron, and blood through the open areas of skin leads to hypoalbuminemia and deficiency of iron and trace minerals. Furthermore, the chronic disruption of the epithelial lining of the small intestine leads to gross malabsorption of nutrients, and the pain with ingestion of food decreases intake. Consultation with a nutritionist is important to maximize caloric and protein intake and provide specific nutrients and vitamins such as iron, zinc, and vitamin D ₃ . High consumption of milk products can serve as a source of protein, calcium, and vitamin D, and is important because 64% of patients with generalized severe RDEB are osteoporotic. The reduction in bone mineral density results from the combination of poor nutrition, decreased ultraviolet exposure, reduced mobility and weight-bearing, and delayed puberty. Noncontact sports are recommended to strengthen muscles and bones; more physically active children tend to have more autonomy and less dependency on a wheelchair. Food aversion, especially for children who predominantly use their gastrostomy as a source of nutrition, is a confounding factor; speech therapists can help teach children to eat (a complication of early gastrostomy use). Oral iron may be poorly tolerated by the gastrointestinal tract, and constipation is a potential issue; intravenous administration of iron or blood transfusions may be needed to maintain a hemoglobin (Hgb) level of at least 8 g/dL in severely affected children. Soft nipples such as the Haberman feeder should be used, with the opening enlarged to minimize the need for sucking. The lips should be protected with petrolatum before initiating feeding. In general, nasogastric tube feeding should be avoided, or if necessary, a tube suitable for long-term feeding should be used. Placement of a button gastrostomy tube should be considered in infants who start to drop off their growth curve as a means of supplemental feeding to increase caloric intake and as an alternative route to oral feeding, especially for severe generalized forms of JEB and RDEB. Twice-yearly dental visits are recommended, and daily care is important to decrease the risk of caries; teeth can be cleaned with soft, moist gauze or a soft toothbrush and rinses of chlorhexidine ; some advocate for use of an enamel-promoting toothpaste (such as MI Paste). Endosseous implants have been placed successfully in patients with EB.

Dysphagia is the major symptom of esophageal involvement in RDEB. It may result from a reversible inflammatory reaction or from a permanent stricture. Barium studies demonstrate esophageal lesions; endoscopy, however, is not recommended. Softening of the diet for several weeks may result in modest to marked improvement of symptoms. If conservative management fails to result in proper nourishment, esophageal dilation, ideally through fluoroscopic guidance, should be performed and may be repeated if stenosis recurs. Esophageal perforation is the most serious complication of dilation. Surgery is an alternative, through colonic interposition and resection of localized strictures with end-to-end anastomosis, but the procedures carry a high risk. Gastroesophageal reflux may be exacerbated by esophageal dilation but responds to medical management with thickening of the milk, histamine 2 receptor (H2)-blockers, proton pump inhibitors, or promotility agents. Constipation is usually managed by maintaining adequate fluid intake and dietary fiber and by administering laxatives such as polyethylene glycol 3350 (MiraLAX). Restoration of function in severe fusion and flexion deformities of the hands and feet can often be helped by physiotherapy and appropriate plastic surgery, especially to separate the thumb and straighten digits. However, partial recurrence is the norm, especially on the nondominant hand. Healing in these “degloving” procedures may be facilitated by application of biologic dressings with the tissue-engineered skin substitutes and epidermal grafts to the wounds.

Individuals with EB may have “revertant mosaicism,” in which a second gene change in a localized area leads to functional and clinical normalization (see Fig. 13.30 ), ^, or nonrevertant mosaicism, in which a gene change in some, but not all, somatic cells either leads to a mosaic dominant disorder (one allele affected) or converts a carrier state into a recessive disorder (both alleles affected) at the involved sites, as has recently been described for RDEB. Detection of normal-appearing skin sites, which are most common in generalized intermediate JEB because of mutations in COL17A1, allows an unlimited source of cultured keratinocytes, fibroblasts, or even iPSCs for stem cell transplantation or for grafting. ^,

Ablative fractional laser resurfacing has shown promising results in managing pseudosyndactyly and accelerating wound healing. Anesthesia management for procedures is complicated, especially given the microstomia of RDEB, but may include mask anesthesia, endotracheal tube, intravenous sedation, and local anesthetic blocks. ^,

Clinical surveillance through complete skin examination should be performed starting in later adolescence to search for SCCs. Self-monitoring should also be taught with photography, especially because full examination at the medical visit is sometimes challenging. Wounds that fail to heal or appear atypical, especially in affected adults, deserve biopsy to consider the possibility of SCC. Guidelines for best practices related to surveillance and diagnosis, tumor evaluation, surgical and nonsurgical treatment, use of prosthetics, and end-of-life care were published in 2016. Of paramount importance is psychological support after a diagnosis of SCC is made. Early intervention using full-thickness excision with wide margins is usually first-line therapy. ^{, ,} Mohs surgery offers no long-term benefit in decreasing local recurrence, metastases, or death. Amputation is required in 42% of patients with RDEB and SCC, with approximately equal outcomes on the hands and legs. Surgical debulking and radiation therapy are palliative to reduce pain or bleeding, but radiation should be delivered in small fractions to reduce the risk of skin desquamation. The benefit of chemotherapy may be outweighed by the risks, and use should be considered carefully. Cetuximab (epidermal growth factor receptor [EGFR] antagonist) has controlled SCC metastasis and may be of benefit for palliation in advanced cancer. ^,

Management of EB represents a huge unmet need, and several experimental approaches are currently being investigated. These range from gene therapy with grafting, to protein replacement, to trying to accelerate wound healing or reduce fibrosis ( Box 13.1 ; details in online version).

Box 13.1

Experimental Approaches for Treating EB (see Online Details)

• Gene therapy

  • Grafting after gene correction or replacement (viral, nonviral)

  • Grafting through expansion of revertant mosaic cells

  • Stem cell transplantation

  • Intradermal injection of gene-corrected fibroblasts

  • Topically applied gene therapy

• Cell therapy

  • Intradermal injection of allogenic fibroblasts

• Pharmacologic approaches

  • Readthrough for null mutations (topical, intravenous gentamycin)

  • Protein replacement therapy (recombinant type VII collagen)

  • Inhibition of inflammatory cytokines

  • Fibrosis reduction

  • Acceleration of wound healing