Pediatric Epidermolysis Bullosa

Epidermolysis bullosa (EB) is a rare group of inherited disorders that manifests as blistering or erosion of the skin and, in some cases, the epithelial lining of other organs, in response to little or no apparent trauma. See the image below.

See 13 Common-to-Rare Infant Skin Conditions, a Critical Images slideshow, to help identify rashes, birthmarks, and other skin conditions encountered in infants.

More than 30 types of epidermolysis bullosa have been described, rendering categorization of the types controversial and often confusing. An international consensus meeting in Vienna, Austria in 2008 reaffirmed the following currently used names for the four major types of epidermolysis bullosa[1] :

• Epidermolytic - Epidermolysis bullosa simplex (EBS)

• Lucidolytic - Junctional epidermolysis bullosa (JEB)

• Dermolytic - Dystrophic epidermolysis bullosa (DEB)

• Multiple levels of blistering - Kindler syndrome

These major types were based on the precise ultrastructural level at which the split responsible for blistering occurs. The leading authority on epidermolysis bullosa added Kindler syndrome as the fourth major epidermolysis bullosa type in 2008 with a unique clinical phenotype—photosensitivity.[1]

The three main types of epidermolysis bullosa were clinically and histologically delineated by the 1960s.[2] In the 1970s, electron microscopy revealed abnormal epidermal keratin filaments in epidermolysis bullosa simplex, disordered dermal anchoring fibrils in dystrophic epidermolysis bullosa, and defective hemidesmosomes in junctional epidermolysis bullosa. Antigens identified with immunohistochemistry in the 1980s[3, 4] led to discovery of the major epidermolysis bullosa genes in the 1990s.[5, 6, 7]

The identified genes include those that encode keratins 5 and 14 in epidermolysis bullosa simplex, collagen VII in dystrophic epidermolysis bullosa, and laminin 5 in Herlitz junctional epidermolysis bullosa. Toward the end of millennium, as the complex structure of desmosomes and hemidesmosomes was unraveled, the genes responsible for the rare subtypes were found, including those that encode α6β4 integrin in epidermolysis bullosa with pyloric atresia, plectin in epidermolysis bullosa with muscular dystrophy, and plakophilin in epidermolysis bullosa with ectodermal dysplasia.

During the past few years, systemic data collection and analysis have been performed on several thousands of patients with epidermolysis bullosa worldwide, and more than 1000 mutations, encompassing more than 10 structural genes, have now been documented. More has been learned about the molecular basis of epidermolysis bullosa, a group of diseases that shares clinical or molecular features with several other genodermatoses. 

Eponyms associated with different forms of epidermolysis bullosa include the following:

• Dowling-Meara

• Köebner

• Weber-Cockayne

• Kallin

• Mendes de Costa

• Herlitz

• Ogna

• Carmi

• Cockayne-Touraine

• Pasini

• Hallopeau-Siemens

• Shabbir

• Laryngoonychocutaneous (LOC)

Cytolysis causes blisters in the epidermis or basement membrane zone of the skin. In epidermolysis bullosa simplex, cytolysis causes blisters in the basal or spinous layers of the epidermis, and keratinocytes often have abnormal density and organization of keratin filaments. In junctional epidermolysis bullosa, the epidermis separates from the basal lamina, forming a blister cavity in the plane of the lamina lucida, where hemidesmosome structure and density are frequently diminished. In dystrophic epidermolysis bullosa, the basal lamina remains attached to the epidermis, but the blister cavity forms beneath the lamina densa of dermoepidermal junction, and anchoring fibrils may appear abnormal, reduced in number, or altogether absent.

Frequency

United States

The exact prevalence of epidermolysis bullosa is unknown. Mild variants have been estimated to occur as frequently as 1 per 50,000 births. The more severe varieties are believed to occur in 1 per 500,000 births annually.

Between 1986 and 2002, the National Institutes of Health (NIH) funded the National EB Registry (NEBR), a cross-sectional and longitudinal epidemiological study of epidermolysis bullosa patients across the entire continental United States. Nearly 3300 epidermolysis bullosa patients were identified, enrolled, classified, clinically characterized, and followed for outcomes. The incidence and prevalence of epidermolysis bullosa was estimated at approximately 19 cases per 1 million live births and 11 cases per 1 million population.[8, 9] These data were then used to estimate carrier frequencies for epidermolysis bullosa within the United States, which is between 1 in 300 and 1 in 800.[10]

The prevalence of inherited epidermolysis bullosa subtypes in the United States in January 2002, based on the NEBR was as follows[9] :

• Epidermolysis bullosa simplex - 6 cases per 1 million population
• Junctional epidermolysis bullosa - 0.49 case per 1 million population
• Dominant dystrophic epidermolysis bullosa - 1.49 cases per 1 million population
• Recessive dystrophic epidermolysis bullosa - 1.35 cases per 1 million population

The incidence of inherited epidermolysis bullosa subtypes in the United States from 1986 to 2002, based on the NEBR was as follows[9] :

• Epidermolysis bullosa simplex - 7.87 cases per 1 million live births
• Junctional epidermolysis bullosa - 2.68 per 1 million live births
• Dominant dystrophic epidermolysis bullosa - 12.12 per 1 million live births
• Recessive dystrophic epidermolysis bullosa - 3.05 per 1 million live births

International

The point prevalence of all forms of epidermolysis bullosa in Scotland was 49.0 cases per million, comprising epidermolysis bullosa simplex at 28.6 cases per million and dystrophic epidermolysis bullosa at 20.4 cases per million population.[11]

The incidence rate of new cases of epidermolysis bullosa diagnosed per year in Northern Ireland during a 23-year period (1962-84) is 1.4 cases per million and the prevalence of all forms estimated at 32 cases per million population. The prevalence of simplex, junctional, and dystrophic forms is 28 cases, 0.7 case, and 3 cases per million population, respectively.[12]

The estimated prevalence of each type of epidermolysis bullosa in Japan was as follows: simplex type, 2.9-4 cases per million population; junctional type, 0.15-0.20 cases per million population; dominant dystrophic type, 1.1-1.5 cases per million population; and recessive dystrophic type, 1.5-2.1 cases per million population.[13]

The prevalence of epidermolysis bullosa in Croatia, Yugoslavia, from 1960-1987 was 9.5 cases per million population.[14]

In the United Kingdom, prevalence rates of epidermolysis bullosa have been estimated to range from 15-32 cases per million population.[11, 12, 15]

Data from the Australasian EB Registry provided a prevalence estimate of 10 cases per million live births.[16]

Race

The epidermolysis bullosa simplex Ogna variant has been described in Norwegian individuals.

Sex

Epidermolysis bullosa is an autosomal inherited disorder. The incidence does not differ by sex.

Age

The onset of epidermolysis bullosa simplex is at birth or early infancy. The onset of junctional epidermolysis bullosa is at birth. The onset of dystrophic epidermolysis bullosa is at birth or early childhood. The onset of Kindler syndrome is usually within the first year of life.

Epidermolysis bullosa is chronic. Patients should restrict and modify their activity to avoid the serious complications of blistering. Depending on the type of epidermolysis bullosa, disease severity may range from occasional mild blistering of the hands and feet to severe and widespread formation of bullae. These lesions may result in nonhealing erosions, infection, scarring, and joint contracture. Mortality is also related to the abnormalities or anomalies associated with epidermolysis bullosa.

Epidermolysis bullosa continues to be devastating disease with high incidence of aggressive squamous cell carcinoma (SCC). SCC is the most serious complication of epidermolysis bullosa within adults, especially those with Hallopeau-Siemens recessive dystrophic epidermolysis bullosa. By mid adulthood, nearly all patients have had at least one SCC, and nearly 80% die from metastatic SCC.[17] recessive dystrophic epidermolysis bullosa SCC is highly aggressive and has early metastatic spread. Recessive dystrophic epidermolysis bullosa SCC most commonly occurs in chronic nonhealing ulcers and over bony prominences on limbs where UV light exposure is minimal. Unlike most cancers, recessive dystrophic epidermolysis bullosa SCC is generally well-differentiated but behaves in a highly aggressive manner and has high metastatic potential.[18]

Risk of death from renal disease is noted. Causes include renal failure, poststreptococcal glomerulonephritis, secondary amyloidosis, and chronic mechanical obstruction. The cumulative risk of death from renal failure among patients with Hallopeau-Siemens recessive dystrophic epidermolysis bullosa is 12.3% by age 35 years.[19]  Death may occur during infancy or early childhood, due to sepsis, renal failure, upper airway occlusion, or failure to thrive.[19, 20]

Healing of dystrophic epidermolysis bullosa results in dystrophic or scarring change. In epidermolysis bullosa simplex, when blisters cleave in the epidermis, healing occurs without scarring. In junctional epidermolysis bullosa, when blisters cleave below the epidermis but above the basal lamina, blistering leads to mild atrophic changes.

Important findings in epidermolysis bullosa (EB) include the age of onset; the size, frequency, and location of blisters; and the possible inciting factors (eg, heat, trauma).

Check for a family history of blistering disease and for the patient's geographic and racial ancestry. Evaluation of any patient with suspected epidermolysis bullosa should include mapping of the family's pedigree. However, an absence of affected family members does not, by itself, establish that the mode of transmission is autosomal recessive because apparently isolated cases can be due to spontaneous mutation or incomplete penetrance of an autosomal dominant trait.

Review of systems should include a search for mucosal involvement, including oral, nasopharyngeal, ocular, genitourinary, GI, and respiratory symptoms.

Perform a complete physical examination with emphasis on inspecting all skin areas and mucosal surfaces. Evaluate the size, location, and character of the blisters and determine the level at which the blister forms.

Examine the patient for involvement of the nails, hair, or teeth.

Areas prone to blistering due to pressure, trauma, or excessive heating include the fingers, hands, elbows, feet, legs, and diaper area (in infants). See the images below.

Congenital localized absence of skin is now known to be a phenotypic pattern that neonates with any major form of epidermolysis bullosa may demonstrate at birth. See the images below.

Genetics

Most subtypes of epidermolysis bullosa simplex (EBS) are autosomal dominant disorders; rare patients with autosomal recessive have been reported.[21]

Junctional epidermolysis bullosa (JEB) is an autosomal recessive disorder.

Dystrophic epidermolysis bullosa (DEB) is either autosomal dominant or autosomal recessive.

Kindler syndrome is an autosomal recessive disorder.[22]

Types of epidermolysis bullosa and associated characteristics are outlined in the tables below.[23]

Table 1. Morphologic and molecular features of Major Types and Subtypes of Epidermolysis Bullosa (Open Table in a new window)

Table 2. Major Epidermolysis Bullosa Types and Subtypes (Open Table in a new window)

Table 3. Mutational Analyses and Inherited Epidermolysis Bullosa ^{[24, 25, 26]} (Open Table in a new window)

Table 4. Major Epidermolysis Bullosa Subtypes and Their Targeted Proteins (2008 International Consensus Report ^[27] ) (Open Table in a new window)

Complications include the following:

• Secondary infections (eg, pseudomonal, staphylococcal, beta-hemolytic streptococcal, and herpes organisms)[28]

• Mitten deformities (pseudosyndactyly) of the fingers and toes[21]

• Scarring of the skin

• Pigmentary changes

• Anonychia

• Dental anomalies

• GI complications: These may arise within the esophagus, stomach, small and large intestines, rectum, and anus. Esophageal stricture and growth retardation are commonly reported in patients with the more severe epidermolysis bullosa subtype.[29, 30, 31]

• Genitourinary tract complications: These include urethral meatal stenosis, urinary retention, bladder hypertrophy, hydronephrosis secondary to ureteral strictures, pyelonephritis, and cystitis. The complications occur in a minority of patients across all major epidermolysis bullosa subtypes, with the highest frequency seen in Herlitz junctional epidermolysis bullosa (JEB-H).[32, 33]

• Ocular diseases: Ocular diseases in epidermolysis bullosa include corneal erosions or blistering, corneal scarring, cornea opacity, cornea ulcerations, symblepharons, blepharitis, ectropions, red watery eyes, photophobia, conjunctival injection, conjunctival edema, limbal broadening, pannus formation, ectropions, ocular pain, lacrimal duct obstruction, impair vision, and blindness.[34] The most common complications include corneal erosions and blisters, and frequencies mirror relative severity of the skin disease.

• Ear, nose, and throat: These complications include tracheolaryngeal stenosis or stricture, chronic otitis media, chronic otitis externa, and hearing loss.[35]

Transmission electron microscopy

Electron microscopy determines the level of skin cleavage in epidermolysis bullosa (EB) and permits visualization and semiquantitative assessment of specific structures, which are known to be altered in selected epidermolysis bullosa subtypes. See the image below.

Very few highly proficient electron microscopy laboratories are now available worldwide.

Immunofluorescence mapping (IFM)

IFM is as diagnostically reliable as transmission electron microscopy for several type of epidermolysis bullosa. IFM, when coupled with the use of specific monoclonal antibodies, can provide considerable insight into not only the major type of epidermolysis bullosa but also into the structural protein most likely mutated.

Mutation analysis

Mutation analysis is the ultimate means of determining the mode of inheritance and the precise site and type of molecular mutation. It is the recommended technique; prenatal and preimplantation diagnosis can be performed. It is very labor intensive and expensive to perform, currently only a few research or commercial laboratories are equipped to perform this analysis.

Radiography may indirectly help in diagnosis of certain types of epidermolysis bullosa with associated abnormalities, such as pyloric atresia (PA) or genitourinary obstruction. See the images below.

Electron microscopy in the 1970s revealed abnormal epidermal keratin filaments in epidermolysis bullosa simplex (EBS), disordered dermal anchoring fibrils in dystrophic epidermolysis bullosa, and defective hemidesmosomes in junctional epidermolysis bullosa. Epidermolysis bullosa has approximately 30 different subtypes.

For other microscopic features, see Causes in Presentation.

The treatment of epidermolysis bullosa (EB) is primarily preventive and supportive. Once blistering has occurred, the blister should be punctured with a sterile needle or a blade. This may prevent the accumulation of fluid and pressure and may thus prevent the blister from extending. Complete and gentle drainage of the fluid, accomplished by leaving the roof of the blister intact and by covering the affected area with white petrolatum–impregnated gauze, helps to promote an environment most optimal for healing. If the blister repeatedly refills with fluid, it should be drained several times.

Open wounds should be covered with nonadherent dressings such as petrolatum-impregnated gauze, hydrogels, fenestrated silicone dressings or absorbent foam silicone dressings. Tape and any significant pressure to the skin must be avoided. Dressings can be held in place with rolled gauze (such as Kerlix), with tape applied only to the dressing itself or by stockinette (such as Surgifix or Spandage).

Some authors recommend daily application of polymyxin, bacitracin, or silver sulfadiazine topical ointments to treat open or partially healed wounds, which should be covered with petrolatum-impregnated gauze or nonadherent synthetic dressing. Gentamicin soaks (480 mg/L saline), acetic acid soaks (white vinegar), and the addition of small amounts of bleach to the bath water (eg, 1/8 cup per full tub) have been used to decrease the overgrowth of pseudomonas and staphylococcal organisms.

Corrective gene therapy is the ideal therapy for epidermolysis bullosa, but much more research is required before it can be developed and used in clinical practice. Cell-based therapies using fibroblasts and bone marrow cells have attracted considerable attention.[36]

A randomized, double-blind, placebo-controlled trial determined that low-dose topical calcipotriol helped wounds close more quickly and significantly reduced pruritus.[37]

Mental health

Chronic anticipatory anxiety is a common problem in children with epidermolysis bullosa, especially as it relates to frequent wound care changes. There may be a negative effect on development, mental health, education, family relationships, and, potentially, brain function. Approximately 80% of patients with epidermolysis bullosa experience psychiatric symptoms, particularly anxiety, depression, and behavioral problems. Psychiatric screening should be incorporated into the multidisciplinary approach to the patient with epidermolysis bullosa.[38]

Surgical procedures can correct the deformities of epidermolysis bullosa caused by repeated episodes of blistering and scarring of the hand. Ablative fractional laser surfacing has shown positive preliminary results in the management of dentition, pseudosyndactyly, and wounds. Unfortunately, most therapeutic improvements are often temporary because the recurring scars often require repeated procedures.[39] Esophageal dilatation or insertion of a gastrostomy tube may be required if esophageal strictures develop.

Patients with limited donor sites for a skin graft may need advanced therapy with bioengineered skin products. Several products (eg, composite cultured skin [CCS], Graftskin, Dermagraft) have been used in the treatment of patients with epidermolysis bullosa.

A multidisciplinary team should perform a review in patients with epidermolysis bullosa to address the following issues:

• Regular skin care and dressing

• Pain management

• Nutrition

• Monitoring of blood levels

• Physiotherapy

• Dental treatment

• Occupational therapy

• Videofluoroscopy, barium swallow study, or both

• Echocardiography

When necessary, an ophthalmologist, a gastroenterologist, and plastic surgeon should be consulted.

Patients with extensive cutaneous injury require increased energy (caloric) and protein intake. Vitamin and iron supplements are advised if nutritional compromise is present. If esophageal strictures develop, a blenderized diet is recommended.

Patients should avoid unnecessary trauma to the skin. Wearing loose-fitting clothing and soft, well-ventilated leather shoes is advisable. Because increased ambient temperatures exacerbate most forms of epidermolysis bullosa, a cool environment is important.

A water mattress and soft fleece covering help to limit the friction and trauma that lead to blistering.

Avoid directly taping to the skin.

Keeping the palms and soles cool and dry during hotter weather helps to minimize blistering, especially in the Weber-Cockayne type of epidermolysis bullosa simplex (EBS).

The baby should not be placed in an incubator unless reasons of prematurity prevent open crib, as heat and humidity place the baby at risk for blistering.[40]

Suctioning, nasally and orally, should be avoided. If necessary, a soft catheter should be used with minimal suction pressure.[40]

The umbilical cord should be secured with ligature, not a plastic clamp that can cause friction.[40]

The name band should be placed on clothing and not in contact with skin.[40]

Electrodes should be lubricated, with smallest diameter, and secured with a nonadhesive dressing.[40]

Thick padding should be applied between patient and blood pressure cuff.[40]

Encourage skin-to-skin contact with caretakers.[40]

Surgical procedures for other conditions require special considerations in pediatric EBS patients.[41]

Preventive measures are the key to successful management of epidermolysis bullosa (EB). Epidermolysis bullosa requires cooperation of patients, parents, and physicians caring for the patient.

Medical surveillance for involvements of kidney, urinary tract, eye, and GI tract should become part of the routine evaluation of children and adults with epidermolysis bullosa.

Drug therapy is not currently a component in the standard of care for epidermolysis bullosa (EB). See Treatment.