CASE #1: Epidermolysis bullosa

Epidermolysis bullosa (EB) forms three genetically different inherited disorders; they include simplex, junctional and dystrophic bullosa. All three types share some major features: genetic transmission, blister formation, and fragility of the skin. The main difference between the three is in the ultrastructural site of blister formation in the skin.

EB was originated by von Hebra in 1870. It was first known as erblichen pemphigus. It was not until 1886 that Koebner established the current name for the disorder. Dystrophic epidermolysis bullosa (DEB) was clinically distinguished only in 1898 by Hallopeau. Finally in 1962, Pearson came up with precise characterization utilizing transmission electron microscopy; this allowed the specific branching of the three types of EB.1,2

In the early 1990s, research was done on the specific subtypes of EB at the molecular level. In the United States alone, there are about 8.22 cases for every one million citizens; this number is based on all three types of EB. An analysis of carrier frequency has revealed the prevalence and incidence of dominant dystrophic EB and recessive dystrophic EB as 0.92 and 2.04, respectively.3 These numbers are similar across the world regardless of geographic area or race.

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All three forms of EB are the result of a genetic mutation that occurs on at least 10 different genes, all of which encode for structural proteins. The structural proteins are located in the uppermost papillary dermis, at the dermo-epidermal junction, and within the epidermis. Dystrophic EB is a disorder transmitted either dominantly or recessively. Recessive dystrophic EB (RDEB) occurs when the type VII collagen gene undergoes a compound heterozygous mutation. The mutation results in a premature stop codon, which causes the protein to be truncated. This type of mutation can lead to undetectable levels of anchoring fibrils, causing a very severe form of the disease known as Hallopeau-Siemens. Patients with RDEB have an increased susceptibility to squamous cell carcinoma, thus extra attention needs to be given during skin examinations. Dominant dystrophic EB (DDEB) is caused by a dominate-negative mutation within the type VII collagen gene. This type of mutation does not cause the protein to be truncated, but rather the mutation affects the glycosylation sites. This causes the protein to be abnormal in structure, contributing to blistering within the sublamina densa and a reduced amount of and/or rudimentary appearance of anchoring fibrils.3

Dystrophic EB has both cutaneous and extracutaneous clinical features. All forms of inherited EB are characterized by the presence of tense fluid-filled blisters, erosions, and crusting. Blisters develop within minutes after minimal trauma, such as lateral or rotary traction on the skin, particularly in RDEB. DDEB is the only form of the disease in which mechanically induced blisters are difficult to achieve. Both the recessive and dominant subtypes of dystrophic EB are present at or shortly after birth. DDEB primarily involves the extensor areas of the extremities and the dorsum of the hands. Areas most commonly involved in infants with RDEB include hands, feet, buttocks, scapulae, face, occiput, elbows, and knees. While atrophic scarring may be seen in all forms of EB, it is found in virtually every patient with RDEB. Other clinical features include nail dystrophy or absence, milia, and scarring alopecia of the scalp.

The extracutaneous sites that are affected in DEB include the external surfaces of the eye, the oral cavity, GI tract (not including the stomach), and the genitourinary tract. These surfaces are susceptible to scarring, ulcers, blisters, and erosions.3 Scarring of the eye may result in blindness. Scarring can occur on the esophagus, and if untreated, complete obstruction may occur. Involvement of the small intestine can lead to malabsorption of nutrients. If the large intestine is affected, severe constipation as well as anal fissures can result. Ureteral reflux and hydronephrosis will occur in patients who suffer from recurring blistering of the genitourinary tract.2

Sophisticated staining techniques need to be employed to study and analyze DEB. Light microscopy is of no use to distinguish between the various forms of inherited EB. This is primarily because it is difficult to distinguish between lower intraepidermal and subepidermal blister formation. It is also difficult to distinguish between intralamina lucida and sublamina densa, which help in determining between junctional EB and dystrophic EB, respectively. Transmission electron microscopy (TEM) and immunofluorescence antigenic mapping are both very effective in studying EB and determining the exact level of blister formation in the various subtypes. For all phenotypes of DDEB and RDEB, the level of skin cleavage is at the sublamina densa. TEM identifies the ultrastructural level of blister formation and quantitatively and qualitatively assesses structures such as basilar tonofilaments, hemidesmosomes, sub-basal dense plates, anchoring fibrils, and anchoring filaments.4 When coupled with the use of selected anti-basement membrane monoclonal antibodies, antigenic mapping can qualitatively or semiquantitatively assess expression of specific skin-associated proteins. Direct immunofluorescence for immunoglobulin and complement deposition is negative in all forms of EB except for EB acquisita. Histologically, EB appears as a cell-poor epidermal blister. Sparse perivascular lymphocytes may also be seen.

Clinical findings alone are often insufficient for accurately differentiating EB from other diseases that cause blistering and have similar features. There is a very limited differential diagnosis for a patient with an obvious inheritable blistering disease based on family pedigree and cutaneous findings. However, if family pedigree and history are not available, one must consider such known autoimmune bullous diseases as linear immunoglobulin A bullous dermatosis, pemphigoid, pemphigus, and EB acquisita.1 Other genodermatoses associated with blisters during the neonatal period include sucking blisters and bullous mastocytosis; such infectious diseases as bullous impetigo, staphylococcal scalded skin syndrome (SSSS), and herpes simplex should also be ruled out.5,6

Today, there are no treatments for any type or subtype of inherited EB. Research is being done with gene therapy, which may one day become available for patients suffering from DEB. Avoiding mechanical trauma to the skin is key, and this may be accomplished by using padded bandages and loose-fitting clothing. There are now a number of artificial dressings for chronic skin wounds, most consisting of a hydrocolloid with an absorbent inner layer. Vaseline-impregnated sterile gauze may be used for noninfected wounds. Applying topical antibiotic ointments or creams may also help to minimize infection.

Regular skin examinations are essential to monitor for development of cutaneous malignancies, the leading cause of death in EB patients, occurring at or after mid-adolescence. Most of the extracutaneous complications of DEB can be managed surgically or medically. Aggressive nutritional supplementation can help with malnutrition. This is frequently done through gastrostomy feedings, especially if there are esophageal complications. Surgical degloving and skin grafting may help ease hand deformities.2 Such dental problems as deformity of the primary and secondary teeth may be overcome by using dental braces and crowns. Depression and suicide are also common; a psychiatrist specializing in victims of debilitating diseases is strongly advised. Unfortunately, many of the symptoms and complications do recur over time as the disease progresses.

Given this patient’s clinical picture and family history, DDEB was suspected. Genetic counseling was provided to the parents, explaining that the risk of the disorder in future siblings is 50%. The patient was treated with palliative care, with particular attention paid to avoidance of trauma, local wound care, control of secondary infection, and pain management. She will be monitored for future disease progression, since the clinical course may be variable, especially during the neonatal and infantile periods. Immunofluorescent mapping and monoclonal antibody studies will establish a definitive diagnosis.