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Inherited epidermolysis bullosa: This dermal disease is beyond skin deep

Manifestations of this rare skin disease range from chronic cutaneous erosions to a debilitating breakdown of the skin. More severe variants of the disease can affect all organ systems.

Ryan J. Keefe, MPAS, PA-C

Ryan Keefe is a physician assistant at the Regional Medical Center of San Jose, California. He has indicated no relationships to disclose relating to the content of this article.

Inherited epidermolysis bullosa (EB) is a rare skin disease that manifests as painful cutaneous erosions and blistering following minor skin trauma. Severe debilitation and pain can result when EB affects the gastrointestinal, oral/dental, ophthalmologic, musculoskeletal, and hematologic systems, as it may in patients with recessive autosomes and more severe disease. In the most severe cases, infection through open wounds and overwhelming sepsis can cause death at birth or shortly thereafter. EB affects males and females equally and occurs in approximately 20 live births per million in the United States. This is slightly greater than twice the disease’s estimated prevalence, and is consistent with the mortality rates seen in the many subtypes of EB.¹

Currently, no effective treatments or cure are available for EB; however, genetic research is providing hope for the future. The triad of wound management, nutritional support, and infection control is the standard treatment for patients with the disease.² When a PA encounters a patient with a form of EB, the disease will most likely already have been diagnosed; however, having a basic knowledge of EB can be very beneficial to both the PA and the patient.

HISTORICAL PERSPECTIVE

The term epidermolysis bullosa hereditaria was first used by Koebner in 1886 to describe multiple generations of a family with traumatic skin blistering.³ Ten years later, Hallopeau became the first dermatologist to distinguish between two forms of the disease: EB simplex (EBS) and dystrophic EB (DEB).² EBS lesions form within the epithelium and are nonscarring, whereas DEB lesions are subepithelial and associated with scarring and milia.⁴ These were thought to be the two types of EB. In 1935, however, Herlitz described 24 patients who had hemorrhagic blisters, an absence of scarring, and died before age 3 months from EB letalis.⁴ This type is distinct from the other two types of EB and is more commonly referred to as junctional EB (JEB).⁴ JEB was found to occur at the junction between the basal plasma cell membrane and the basement membrane of the skin.

In the early 20th century, the different types of EB were categorized by their different clinical features. In 1921, Siemens showed associations between Mendelian dominant inheritance and EBS, and recessive inheritance and DEB.¹ JEB has also been shown to be recessively inherited, but with many phenotypical manifestations.⁵ With the exception of autosomal dominant DEB (DDEB), the recessive types of EB are generally more severe than the dominant types.

The advent of electron microscopy allowed dermatologists to distinguish between EBS, JEB, and DEB based on the ultrastructural level in relation to the basement membrane zone (BMZ) where split or separation occurred.⁶ Likewise, genetic research has furthered our understanding of EB. Finding the genetic basis for the various EB types is the foundation for understanding why the disease occurs and where a potential cure could lie. In 1991, researchers discovered that mutations in the keratin 5 and keratin 14 genes cause the majority of EBS types.⁷ Similarly, a number of independent researchers found that DEB is caused by a mutation in the gene encoding for the anchoring fibril-specific protein, type VII collagen.¹ However, JEB shows great genetic variation, as there are at least seven different BMZ components serving as candidate genes for this disorder.²

ANATOMY OF A DISEASE

Human skin is composed of three layers: the epidermis, or outer layer; the dermis, or middle layer; and the deep, subcutaneous layers. The epidermis and the dermis meet at the BMZ, a tissue composite of different molecules that must be intact in order for the cells of the epidermis to attach to the strong fibers of the dermis⁴ (see Figure 1). Each EB type is identified by the layer at which the characteristic blistering occurs. EBS blistering occurs within the epidermis, with BMZ and dermal elements playing a minor role in the mechanical fragility of the skin.⁴ JEB blistering occurs within the upper portion of the BMZ, at the level of the lamina lucida. Separation occurs within the lower portion of the BMZ, in the lamina densa, and extends into the upper dermis by way of the anchoring fibrils in both recessive DEB (RDEB) and DDEB. The defect to type VII collagen causes the instability in this region.⁶

MAKING THE DIAGNOSIS

A diagnosis of EB is made by first obtaining thorough patient and family histories and performing a complete physical examination. Next, the PA should induce blisters by applying rotary traction to an area of clinically unaffected skin with a pencil eraser and then obtain a punch biopsy on the periphery of this blister.⁸ Ideally, samples should be provided for light microscopy, electron microscopy (EM), immunofluorescence microscopy (IF), and cell culture. The gold standard is EM analysis because this technique visualizes the BMZ components, thereby defining the level at which the blistering occurs.⁸ IF can identify the particular molecular defect, as well as provide additional information about the skin level where blistering occurs.

A BREAKDOWN OF EB VARIANTS

EBS is the most prevalent type of EB. According to 1999 United States National EB Registry (NEBR) statistics, 92% of registrants had EBS, 5% had DEB, 1% had JEB, and 2% suffered from an unknown type of EB.¹ Table 1 lists the major types of EB and their most common subtypes, or variants.

Weber-Cockayne variant (EBS-WC) EBS is described as having a mild degree of clinical involvement. Skin lesions heal without scarring, minimal amounts of milia form, and involvement of other organ systems is rare. EBS-WC is localized to the hands and feet. This is the most common variant of EBS—35% of NEBR registrants have EBS-WC. Symptoms usually manifest following an identifiable physical event such as athletic activity or gardening.² This variant is often first diagnosed in infancy or early childhood but, depending on its severity, may not be recognized until adolescence. Blister formation is exacerbated by hyperhidrosis, thereby occurring more often during the summer months.⁴

Koebner variant (EBS-K) The most common generalized EBS variant is EBS-K. Generalized EBS can manifest anywhere on the body. EBS-K lesions are most commonly found on the hands, feet, extremities, face, and trunk.

Dowling-Meara variant (EBS-DM) Also a generalized variant, EBS-DM is characterized by herpetiform groupings of blisters or vesicles and confluent palmar-plantar keratodermas.¹ Intraoral blistering is frequently observed, natal teeth rarely grow, and some patients experience esophageal involvement. Painful blisters and contractures of the feet may prevent normal walking. A distinctive feature of EBS-DM is that heat does not exacerbate blistering, and febrile episodes have even been shown to reduce blistering.⁹ EBS-DM is present at birth, but the characteristic herpetiform lesions may not evolve until later in life, leading clinicians initially to suspect a more severe type.⁴ EBS-DM may be fatal for some neonates, but most will live a normal lifespan.

Herlitz variant (JEB-H) JEB encompasses a wide spectrum of clinical phenotypes, depending on the type of genetic mutation and environmental factors.² Patients with JEB, on the whole, have a higher mortality rate than patients with the other phenotypes. Patients with JEB-H, the most severe form of JEB, generally do not survive past infancy. The mortality rate is an estimated 40% in the first year of life and nearly 100% by age 5 years.² Respiratory failure and sepsis are the two most common causes of death.¹ Patients are severely blistered at birth due to a mutation of the laminin 5 gene, an essential component of the anchoring filaments in the BMZ.⁵ Patients usually have atrophic scarring, dystrophic nails, scalp scarring, alopecia, and periorificial granulation tissue. The teeth are usually eroded due to enamel defects, mucosal surfaces are compromised by chronic erosions, and other organ systems are often involved. Anemia and growth retardation are common sequelae. One of the most troublesome potential complications is tracheolaryngeal blistering and scarring, which can cause stenosis and/or stricture and lead to severe respiratory problems.

Non-Herlitz variant (JEB-nH) In contrast to patients with JEB-H, those with JEB-nH often survive infancy and live a normal lifespan. The disease process has even been shown to slow with age.² Patients with JEB-nH suffer from many of the same cutaneous and extracutaneous manifestations as those with JEB-H, but the disease is less severe. Anemia, growth retardation, and tracheolaryngeal strictures are major concerns in patients with both JEB-H and JEB-nH.¹

Cockayne-Touraine variant (DDEB-CT) DEB, also known as dermolytic EB, is characterized by scarring and milia formation following blistering. DDEB is separated clinically into two variants. DDEB-CT first manifests at birth or in early childhood as severe erosions and blistering. Milia and scarring occur after the blisters heal. Oral lesions are rarely seen, the teeth are usually normal, and nail dystrophy is common in patients with DDEB-CT.⁹ No other significant extracutaneous manifestations have been reported.

Pasini variant (DDEB-P) This variant is distinguished from DDEB-CT by the hypopigmented or flesh-colored papular lesions that appear spontaneously on the trunk or back. However, these albopapuloid lesions have been observed in other EB subtypes and are not pathognomonic.²

Hallopeau-Siemens variant (RDEB-HS) The most significant subtype of RDEB, RDEB-HS is an extremely debilitating and mutilating disease (see Figure 2). Extensive blistering is always present at birth and often the entire skin surface is covered in blisters. Deformities in the extremities are created when nails are lost and recurrent scarring forms “mittenlike” pseudosyndactyly and limb contractures. Blistering occurs on the mucosal surfaces within the mouth, esophagus, and anus. Recurrent scarring around the mouth causes microstomia that, when coupled with an increased incidence of dental caries, makes speaking, chewing, and swallowing difficult.¹⁰ As a result, malnutrition, growth retardation, and chronic mixed anemia commonly ensue.² Ocular involvement is quite common, especially lid and conjunctival scarring. However, the most distressing complication of RDEB-HS is the increased risk of skin cancer at the sites of continuous scarring. The risk of squamous cell carcinoma (SCC) by age 60 years in patients with RDEB-HS is 76.5%, compared to 9% to 14% in healthy males and 4% to 9% in healthy females.¹¹ More than half of all patients with RDEB-HS will develop SCC by age 35 years.¹ SCC often first emerges at puberty or in the early 20s, especially on the extremities and over bony prominences where blistering and scarring occur most often. Nonhealing areas and hyperkeratotic nodules or plaques must be monitored and any suspicious lesions biopsied. Surgical excision is the treatment of choice for SCC.¹¹ Unfortunately, patients with metastases from SCC tend to respond poorly to radiation therapy and chemotherapy.¹²

EXTRACUTANEOUS MANIFESTATIONS

EB can affect the stratified squamous epithelium (SSE) of any organ surface in the body in the same manner as it does the skin. GI organs are the most severely affected. Some degree of GI involvement occurs in more than half of all patients with JEB and in two-thirds of all patients with RDEB.¹ Blistering, erosion, and scarring of the esophagus cause stenosis. Resultant dysphagia and odynophagia lead to malnutrition.⁴ Treatment is directed at minimizing esophageal trauma and blistering. A temporary gastrostomy tube for alimentation is usually tolerated well.⁵ Endoscopic balloon dilatation in severely diseased patients can successfully decrease strictures.¹³ Anal strictures seen in RDEB are treated with laxatives and increased fluid and fiber intake. Chronic constipation and/or fecal impaction are the most worrisome complications. Surgical intervention is usually withheld until late in the disease.

Oral and dental manifestations contribute considerably to poor nutrition and growth retardation in patients with RDEB. The oral mucosa is made up of SSE, so blisters form throughout the mouth, including on the tongue and lips.⁴ With repeated blister formation and subsequent scarring, microstomia and ankyloglossia occur.¹⁴ Some patients may even require surgery to correct the microstomia. Poor dentition is common in patients with EB, especially RDEB and JEB. The tooth enamel is pitted and thin, probably caused by molecular defects in the BMZ-associated proteins in the skin.¹ Maintaining proper dental hygiene is difficult. Routine dental management should start with tooth eruption to preclude developing caries.¹⁵

M. Peter Marinkovich, MD, has found that patients with EB frequently have iron deficiency anemia and reduced total serum proteins (oral communication, January 2005). Patients with EB may not be getting the nutrients needed for erythropoesis from their food because eating is painful. In addition, blood and serum are continuously lost through the constant bleeding and weeping of the lesions.

Blistering and scarring on the eyelids causes ectropion and lagophthalmos, especially in patients with JEB, creating abnormal tear flow that affects eye lubrication.⁴ Corneal abrasions and erosions are common and affect the patient’s vision. Adhesions between the conjunctivae of the lid and eyeball create a symblepharon that limits eye movement. Supplemental lubricating drops are used to prevent drying, and antibacterial ointments prevent infection. Symblepharons may require surgical intervention.

The pseudosyndactyly and limb contractures of RDEB functionally disable the patient. Surgery is often required at an early stage to correct pseudosyndactyly before the fingers become completely obscured. Patients then use splints and dressings to keep the fingers separated. Sadly, most pseudosyndactyly recurs after 5 years.¹ Physical therapy helps patients maintain range of motion and lowers the recurrence rates of these sequelae.

PRENATAL DIAGNOSIS AND GENETIC TESTING

Determining the EB status of a fetus was first possible in 1980. At that time, fetal biopsy techniques were used to obtain samples of fetal skin at 17 to 21 weeks’ estimated gestational age (EGA). The skin could then be examined with EM for EB features.¹⁶ Unfortunately, this technique has a high rate of miscarriage. Chorionic villus sampling (CVS) and amniocentesis permit analysis of fetal DNA for specific genetic mutations at 8 to 10 weeks’ EGA and 11 to 15 weeks’ EGA, respectively.¹ One study demonstrated a 98% success rate for prenatal genetic diagnosis using these methods.⁸ CVS and amniocentesis are now the preferred screening tests because they can be performed at an earlier gestation age, in an outpatient setting, and with fewer complications than fetal skin biopsy.¹

The genetic defect in an affected family must be identified and defined via serum DNA analysis of the parents and/or affected siblings before either screening test is performed.² Once the specific mutation is characterized, genetic counseling can be offered based on the patient’s genotype and mode of inheritance.⁸ An emerging technique is preimplantation diagnosis. In families with known mutations, the EB status is identified before in vitro fertilized embryos are implanted. Then only embryos that are normal or carrier status are implanted in the uterus.¹

THERAPEUTIC MODALITIES

Current treatments Daily dressing changes to keep the skin moist, covered, and cushioned are the mainstay of treatment for EB. A petroleum jelly ointment (Vaseline) is applied to the erosions to reduce friction, protect against transepidermal water loss and infection, and promote wound healing.⁸ Topical antibiotic ointments provide day-to-day infection prophylaxis and should be rotated on a monthly basis to avoid resistance.¹⁷ To dress the skin, cover the ointment-covered area with a nonadhesive gauze pad; wrap the area with tubular gauze; and secure the tubular gauze to itself with paper tape. The tape should never be secured directly to the skin. Blisters should be aseptically lanced and drained, leaving the blister roof intact to act as a natural dressing.¹⁷ Areas of chronic nonhealing can be covered with an artificial skin patch (Apligraf).⁸ Ambient temperature should be below 76¼F because warmth can exacerbate the blistering in all patients with EB except those with EBS-DM.¹⁷

No systemic medications effectively lessen the blistering of EB.² Some patients have claimed to benefit from treatment with phenytoin (Dilantin, Phenytek), but a large trial showed no statistically significant benefit compared to placebo.¹ A limited trial in 2004 showed that high-dose tetracycline may decrease blister counts in patients with EBS-WC; however, potential side effects can be severe.¹⁸ Other systemic therapies have included retinoids, vitamin E, and glucocorticoids. None of these have proven to be effective in long-term trials.⁸ Aggressive systemic antibiotic therapy is necessary whenever there is evidence of extracutaneous bacterial infection.¹

Caregivers must be diligent about providing healthy and complete diets. Like burn patients, patients with EB require increased nutrients to offset the catabolism of their wounds.¹ Recommended diets contain soft or pureed, high-calorie foods. Liquid diets or total parenteral nutrition may be necessary for some patients.¹⁶ Initially, a dietician should assist with creating the patient’s diet. Formulas specifically tailored for calculating energy and nutrient requirements of patients with EB should be followed.¹⁹

Potential therapies Research to find a cure and more effective treatments are ongoing. The majority of research focuses on gene therapy and protein therapy. Protein therapy attempts to replace missing proteins (such as type VII collagen) or correct defective ones by using recombinant techniques and then applying the recombinant directly to the affected skin.⁵ Recombinant cells corrected in vitro are then grafted onto affected sites. This technique was shown to normalize phenotypic abnormalities.⁸ In a recent trial, injecting type VII collagen intradermally into affected skin reversed the features of DEB.²⁰

Similarly, gene therapy restores normal production of structural proteins by delivering genes to replace those that are missing or defective.⁵ However, finding an effective way of delivering the genes to affected sites has been difficult. Genetically corrected cell grafts and gene-carrying modified viruses are promising, but drawbacks include cost, graft fragility, and viral vector safety.⁸ Intradermal injection of gene-modified fibroblasts has been quite successful and does not have the drawbacks of grafting.²¹ Injecting RDEB fibroblasts that are overexpressing type VII collagen into intact RDEB-affected skin simultaneously restores type VII collagen expression and eliminates the cutaneous blistering and anchoring-fibril defects.²²

CONCLUSION

EB is a rare and enormously debilitating, disabling, and frustrating disease. Patients and their families endure infinite amounts of anguish and mental strain. In one study of NEBR registrants, all patients with EB, regardless of type, were found to be at least partially dependent on others for some of their daily activities, particularly walking and personal hygiene.²³ Another study showed that having a child with EB had a profound negative effect on the relationship between parents.²⁴ Strong support networks are imperative to help patients and families cope with this devastating disease. Organizations like DebRA (DEB Research Association) were founded both to raise money for EB research and to provide support for patients and their families.

EB typically manifests early in life as recurrent skin blisters and scarring. Marinkovich explains that, expectedly, most patients receive a diagnosis from a pediatrician, a dermatologist, or an EB clinic; however, subsequent care is managed by primary care clinicians. Optimal management of patients with this disease often requires a multidisciplinary approach. Until a definitive treatment is found, an important part of the care provided by PAs is to ensure that the patient with EB is as comfortable as possible. JAAPA

REFERENCES

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