Pediatrics

Epidermolysis bullosa

OVERVIEW: What every practitioner needs to know

Are you sure your patient has epidermolysis bullosa? What are the typical findings for this disease?

Epidermolysis bullosa (EB) presents with blisters/bullae on the skin in response to minimal trauma. The typical location is on friction-prone areas such as hands, feet, knees, and elbows.

The severity and extent of the blistering depends on the type of EB (see below). The presence of blisters can lead to pain itching and affect daily activities and quality of life.

Classification

There are four major types of EB that result from protein abnormalities affecting the dermoepidermal junction. Lack of production, or production of proteins that are structurally abnormal, leads to fragility of the skin and separation of the skin layers. The clinical presentation, severity, and overall prognosis depends on the level of the split within the dermoepidermal junction.

Epidermolysis bullosa simplex (EBS) results from abnormal production of the proteins that make the desmosomal and hemidesmosomal unit (keratin 5, 14, plectin). Other rare variants of EBS may involve transglutaminase 5, desmoplakin, plakoglobin, plakophilin 1, integrin, exophilin 5, and bullous pemphigoid antigen-1. These mutations lead to blistering above the basement membrane. Most of the forms are autosomal dominantly inherited. Its clinical manifestations are primarily skin related of various severity depending on the EBS subtype. Overall, these patients have a better prognosis than do those with the other forms of EB; long-term survival is unaffected.

Junctional epidermolysis bullosa (JEB), is the result of abnormal proteins (laminin 332, integrin, collagen XVII) that are present at the basement membrane. The most severe subtype, called generalized severe JEB, is characterized by severe skin and mucosal blistering that leads to mortality within the first few years of life. The other forms (generalized intermediate, localized) have milder presentations and are compatible with long-term survival.

Dystrophic epidermolysis bullosa (DEB) is the result of collagen VII mutations that create a split below basement membrane. As the split is lower, the resulting blisters are deeper and heal with scarring. There are two major subtypes, dominant DEB (DDEB) and recessive DEB (RDEB). The recessive forms produce lifetime blistering, significant extracutaneous findings, and decreased survival, particularly in the generalized forms.

Kindler syndrome (KS) is the result of fermitin family homolog 1 (kindlin-1) mutations. It is characterized by blistering at multiple levels within the basement membrane and unique clinical features from other EB types, such as photosensitivity. KS is autosomal recessively inherited. KS produces significant skin findings (blistering is more common in children than in adults) and extracutaneous findings (including oral cavity abnormalities, GI tract abnormalities, pseudosyndactyly). Long-term survival is not commonly affected.

Cutaneous manifestations

Blisters ranging from small to large bullae

Erosions

Hemorrhagic crusts

Chronic wounds

Scars

Contractures

Extracutaneous findings

Mouth

Microstomia

Dental decays

Bleeding gums

Ankyloglossia

Oral ulcers

Eyes

Erosions/blisters

Keratitis

Scarring

Blepharitis

Ectropion

Ear, Nose, Throat

Blisters leading to hoarseness, airway obstruction

Conductive hearing loss

Gastrointestinal Tract

Esophageal blisters/erosions

Esophageal pain/dysphagia

Gastroesophageal reflux

Constipation due to perianal blistering/fissuring

Malabsorption leading to vitamin and mineral deficiencies

Colitis

Genitourinary Tract

Hematuria

Ureteral strictures

Hydronephrosis

IgA nephropathy

Chronic renal failure

Glomerulonephritis

Renal amyloidosis

Heart

Dilated cardiomyopathy (multifactorial)

Anemia (multifactorial: iron deficiency, blood loss through the skin, chronic inflammation)

Osteoporosis (immobility, poor nutrition, skin not exposed because of bandages)

Short stature

Delayed puberty

What other disease/condition shares some of these symptoms?

Newborn Period

Infections (viral, herpes; bacterial; streptoccocus group A/B, staphylococcus species)

Immunoblistering disorders (mother typically affected)

Mastocytosis

Inherited skin disorders (bullous ichthyosis, epidermolytic hyperkeratosis, porphyria, incontinentia pigmenti)

Childhood Period

Infections (herpes, varicella, bullous impetigo, staphyloccoccal scaled skin syndrome, bullous tinea)

Immunoblistering disorders (linear IgA dermatosis, pemphigus, bullous pemphigoid, EB acquisita)

Porphyria

Systemic lupus erythematosus

What caused this disease to develop at this time?

EB is an inherited disorder

It can be autosomal dominant or autosomal recessive

There are at least 14 different types of missing proteins responsible for one of the three major described types

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Skin Biopsy

Light microscopy—level of the defect

Electron microscopy— to identify level of the split and morphologic characteristics of the dermoepidermal structures

Immunofluorescence antigen mapping (IFM)—most sensitive in identifying and quantifying the missing protein

Would imaging studies be helpful? If so, which ones?

Imaging studies are not useful.

Confirming the diagnosis

Rule out other entities with viral and bacterial studies.

Skin biopsy establishes the diagnosis offers some insight into the prognosis, depending on the protein affected (e.g., degree of staining for laminin 332 on immunophenotyping may be predictive of severe, generalized JEB (no staining), or localized variant of JEB [some staining]).

Molecular diagnosis confirms the diagnosis of EB as well as the type and subtype. It can help the clinician with long-term prognosis and can help families with prenatal testing.

If you are able to confirm that the patient has epidermolysis bullosa, what treatment should be initiated?

There is no curative treatment for EB. The goals of management are to prevent blistering, recognize and manage complications and improve quality of life.

Skin Care

Avoidance of sticky tapes and probes directly on the skin (use soft silicone fixation tape to secure devices and use a silicone medical adhesive remover)

Prevention of blistering in the neonatal/infantile period (gentle handling, invert clothing so the seams are on the outside, place monitor probes on silicone dressings instead of on the skin, remove elastic layer of the diaper, use soft silicone nipples for feeding to prevent oral blisters, use "egg crate" mattress or sheepskin on beds)

Prevention of blistering in childhood (soft leather shoes, protective pads around knees, avoid sticky dressings)

Management of open blisters (the fluid can lead to further blistering and causes pain; need to drain fluid by opening the blister with a sterile needle leaving the blister roof intact)

Management of skin wounds

Nonstick silicone dressings

Avoid daily dressing changes to minimize trauma

Exudative wounds require two layers of dressings (contact mesh layer and a secondary dressing to absorb exudate; only the top layer is replaced as needed, the contact one can be left in place for up to 1 week) or a foam dressing

Chronic wounds are colonized with bacteria; use antimicrobial agents topically or silver dressings

Secure dressing in place using a burn net

Avoid routine use of topical antibiotics, particularly the ones with potential sensitization (neomycin, bacitracin)

Soaking in a bathtub may help with the removal of dressings; salt and a cupful of bleach added to the water are helpful in decreasing the skin colonization

Routine bacterial skin swabs are not helpful as they reflect bacterial colonization

Fever, increasing exudate, increasing local pain are indicative of bacterial infection and require systemic antibacterial treatment

Pain/Itch Management

Minimize pain (nonstick dressings, cover open areas, remove dressings in the tub after soaking)

Use opioids (morphine) before dressing changes and any other painful procedures (blood investigations)

Use physical methods (ice packs) to decrease itching

Use sedating antihistamines for itch control

Management of Anemia (depending on the level requires iron supplementation and transfusions)

Ensuring Optimal Nutrition

Ensure caloric needs are met

Provide G-tube feedings if oral intake is restricted

Esophageal dilatation for strictures

Management of Constipation

Stool softeners

Laxatives

Management of Vitamin/Mineral Deficiencies

Calcium and vitamin D supplementation

Iron supplementation

Zinc, carnitine, selenium supplementation depending on the blood levels

Anticipatory Guidance of Complications

Blood investigations yearly or more frequently depending on the symptoms (e.g., complete blood count, iron studies; calcium, phosphate, vitamin D, zinc, carnitine, and selenium determinations; erythrocyte sedimentation rate; C-reactive protein, urea, creatinine, and electrolyte levels)

Bone densitometry (Dexa) scan yearly

Electrocardiogram, echocardiogram yearly

Urinalysis, abdominal ultrasonography

What are the possible outcomes of epidermolysis bullosa?

Prognosis of EB depends on the type and subtype. Generally, EBS, generalized, intermediate JEB, localized JEB, dominant forms of DEB (DDEB), and KS are associated with a better prognosis than is generalized, severe JEB and generalized, severe or generalized, intermediate recessive DEB (RDEB). Mortality in childhood is related to sepsis, airway compromise, and dilated cardiomyopathy, whereas in adulthood it is due to invasive squamous cell carcinoma. The cumulative mortality by age 15 years is 60% for JEB and 8% for recessive DEB.

What causes this disease and how frequent is it?

Genetics are the cause of this disease. The exact prevalence is unknown.

How do these pathogens/genes/exposures cause the disease?

This is a genetic disorder leading to partial or complete loss of structural proteins that are essential for the integrity of the basement membrane, leading to skin fragility.

What complications might you expect from the disease or treatment of the disease?

Chronic anemia

Failure to thrive

Delayed puberty

Osteoporosis

Dilated cardiomyopathy

Squamous cell carcinoma

Are additional laboratory studies available; even some that are not widely available?

Genetic testing

How can epidermolysis bullosa be prevented?

Prenatal testing

What is the evidence?

There is anecdotal evidence only; studies are currently underway.

Bruckner, AL, Bedocs, LA, Keiser, E. "Correlates of low bone mass in children with generalized forms of epidermolysis bullosa". J Am Acad Dermatol. vol. 65. 2011. pp. 1001-9.

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El Hachem, M, Zambruno, G, Bourdon-Lanoy, E. "Multicentre consensus recommendations for skin care in inherited epidermolysis bullosa". Orphanet J Rare Dis. vol. 9. 2014. pp. 76.

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Fine, JD, Mellerio, JE. "Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part II. Other organs". J Am Acad Dermatol. vol. 61. 2009. pp. 387-402.

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Hubbard, L, Haynes, L, Sklar, M. "The challenges of meeting nutritional requirements in children and adults with epidermolysis bullosa: proceedings of a multidisciplinary team study day". Clin Exp Dermatol. vol. 36. 2011. pp. 579-84.

Lara-Corrales, I, Arbuckle, A, Zarinehbaf, S, Pope, E. "Principles of wound care in patients with epidermolysis bullosa". Pediatr Dermatol. vol. 27. 2010. pp. 229-37. http://www.ncbi.nlm.nih.gov/pubmed/?term=20403117.

Lara-Corrales, I, Mellerio, JE, Martinez, AE. "Dilated cardiomyopathy in epidermolysis bullosa: a retrospective, multicenter study". Pediatr Dermatol. vol. 27. 2010. pp. 238-43. http://www.ncbi.nlm.nih.gov/pubmed/?term=20609141.

Luu, M, Cantatore-Francis, JL, Glick, SA. "Prenatal diagnosis of genodermatoses: current scope and future capabilities". Int J Dermatol. vol. 49. 2010. pp. 353-61.

Wagner, JE, Ishida-Yamamoto, A, McGrath, JA. "Bone marrow transplantation for recessive dystrophic epidermolysis bullosa". N Engl J Med. vol. 363. 2010. pp. 629-39.

Ongoing controversies regarding etiology, diagnosis, treatment

Because of the rarity of the disease and the wide spectrum of severity, there are no uniform guidelines of care. In addition, most of the recommended "ideal" dressings are not widely available or affordable. New therapies aimed at correction of the genetic defect are being attempted at present.

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