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Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some cases) that can results in nonscarring blisters caused by little or no trauma. The current classification of epidermolysis bullosa (EB) includes two major types and 12 minor subtypes of EBS; all share the common feature of blistering above the dermal-epidermal junction at the ultrastructural level. The four most common subtypes of EBS are the focus of this GeneReview:
- EBS, localized (EBS-loc; previously known as Weber-Cockayne type)
- EBS, Dowling-Meara type(EBS-DM)
- EBS, other generalized (EBS, gen-nonDM; previously known as Koebner type)
- EBS-with mottled pigmentation (EBS-MP)
In EBS, gen-non DM, blisters may be present at birth or develop within the first few months of life. Involvement is more widespread than in EBS-loc, but generally milder than in EBS-DM.
In EBS-MP, skin fragility is evident at birth and clinically indistinguishable from EBS-DM; over time, progressive brown pigmentation interspersed with hypopigmented spots develops on the trunk and extremities, with the pigmentation disappearing in adult life. Focal palmar and plantar hyperkeratoses may occur.
In EBS-DM, onset is usually at birth; severity varies greatly, both within and among families. Widespread and severe blistering and/or multiple grouped clumps of small blisters are typical and hemorrhagic blisters are common. Improvement occurs during mid- to late childhood. EBS-DM appears to improve with warmth in some individuals. Progressive hyperkeratosis of the palms and soles begins in childhood and may be the major complaint of affected individuals in adult life. Nail dystrophy and milia are common. Both hyper- and hypopigmentation can occur. Mucosal involvement in EBS-DM may interfere with feeding. Blistering can be severe enough to result in neonatal or infant death.
Diagnosis/testing. EBS-loc can almost always be diagnosed clinically. Diagnosis of generalized forms of EBS requires a skin biopsy obtained from the leading edge of a fresh blister; diagnosis is based on immunohistochemistry using appropriate fluorescent antibodies or transmission electron microscopic examination that reveals splitting within or just above the basal cell layer of the skin. . The four most common forms of EBS are caused by mutation in either KRT5 or KRT14. Molecular genetic testing of KRT5 and KRT14 detects mutations in approximately 75% of individuals with biopsy-diagnosed EBS-loc, EBS-DM, and EBS-gen-nonDM, and 90%-95% of mutations in those with EBS-MP. Such testing is clinically available.
Management. Treatment of manifestations: Supportive care to protect the skin from blistering; use of dressings that will not further damage the skin and will promote healing. Lance and drain new blisters. Dressings involve three layers: a primary nonadherent contact layer, a secondary layer providing stability and adding padding, and a tertiary layer with elastic properties.
Prevention of primary manifestations: Aluminum chloride (20%) applied to palms and soles can reduce blister formation in some individuals. Cyproheptadine (Periactin®), tetracycline, or botulimun toxin can reduce blistering in some individuals with EBS. Keratolytics and softening agents for palmar plantar hyperkeratosis may prevent tissue thickening and cracking.
Prevention of secondary complications: Watch for wound infection; treatment with topical and/or systemic antibiotics or silver-impregnated dressings or gels can be helpful. Appropriate footwear and physical therapy may preserve ambulation in children who have difficulty walking because of blistering and hyperkeratosis.
Surveillance: For infection and proper wound healing.
Agents/circumstances to avoid: Excessive heat may exacerbate blistering and infection. Avoid poorly fitting or coarse-textured clothing/footwear and activities that traumatize the skin.
Genetic counseling. EBS caused by mutations in KRT5 or KRT14 is usually inherited in an autosomal dominant manner, but in rare families, especially those with consanguinity, it can be inherited in an autosomal recessive manner.
Dystrophic Epidermolysis Bullosa
DEB,
Epidermolysis Bullosa Dystrophica. Includes: Dominant Dystrophic
Epidermolysis Bullosa; Recessive Dystrophic Epidermolysis Bullosa,
Generalized Other; Recessive Dystrophic Epidermolysis Bullosa, Severe
Generalized
Based on the most recent classification system, dystrophic epidermolysis bullosa (DEB) includes three subtypes: recessive
DEB, severe generalized (RDEB-sev gen) (formerly called
Hallopeau-Siemens type (RDEB-HS); recessive DEB, generalized other
(RDEB-O) (formerly called non-Hallopeau-Siemens type (RDEB-non-HS); and dominant DEB (DDEB). In RDEB-sev gen,
blisters affecting the whole body may be present in the neonatal
period. Oral involvement may lead to mouth blistering, fusion of the
tongue to the floor of the mouth, and progressive diminution of the size
of the oral cavity. Esophageal erosions can lead to webs and strictures
that can cause severe dysphagia.
Consequently, severe nutritional deficiency and secondary problems are common. Corneal erosions can lead to scarring and loss of vision. Blistering of the hands and feet followed by scarring fuses the digits into "mitten" hands and feet, a hallmark of this disorder.
Consequently, severe nutritional deficiency and secondary problems are common. Corneal erosions can lead to scarring and loss of vision. Blistering of the hands and feet followed by scarring fuses the digits into "mitten" hands and feet, a hallmark of this disorder.
The lifetime risk of aggressive squamous cell
carcinoma is over 90%. In contrast, the blistering in the less severe
forms RDEB-O may be localized to hands, feet, knees, and elbows
with or without involvement of flexural areas and the trunk, and without
the severe, mutilating scarring seen in RDEB-sev gen. In DDEB,
blistering is often mild and limited to hands, feet, knees, and elbows,
but nonetheless heals with scarring. Dystrophic nails, especially
toenails, are common and may be the only manifestation of DDEB.
Diagnosis/testing. Examination of a skin biopsy by transmission electron microscopy (EM) and/or immunofluorescent (IF) antibody/antigen mapping is the best way to reliably establish the diagnosis. The only gene known to be associated with DEB is COL7A1. Sequencing of exons 73, 74, and 75 of COL7A1 detects mutations in 75% of families with DDEB; sequencing of all coding exons detects mutations in about 95% of individuals with either DDEB or RDEB.
Management. Treatment of manifestations: New blisters should be lanced, drained, and in most cases dressed with a non-adherent material, covered with padding for stability and protection, and secured with an elastic wrap for integrity. Infants and children with RDEB-sev gen and failure to thrive require attention to fluid and electrolyte balance and may require nutritional support, including feeding gastrostomy. Anemia is treated with iron supplements and transfusions as needed. Other nutritional supplements may include calcium, vitamin D, selenium, carnitine, and zinc. Occupational therapy may help prevent hand contractures. Surgical release of fingers often needs to be repeated.
Surveillance: Biopsies of abnormal-appearing wounds that do not heal or have exuberant scar tissue are indicated for evidence of squamous cell carcinoma beginning in the second decade. Screening for deficiencies of iron, zinc, vitamin D, selenium, and carnitine should start after the first year of life. Routine echocardiograms are recommended to identify dilated cardiomyopathy and bone mineral density studies to identify osteoporosis.
Agents/circumstances to avoid: activities/bandages that traumatize the skin; all adhesives.
Genetic counseling. Dystrophic epidermolysis bullosa is inherited in either an autosomal dominant (DDEB) or autosomal recessive (RDEB) manner. Molecular characterization of pathogenic mutations is the only accurate method to determine mode of inheritance and recurrence risk; phenotype severity and EM/IF findings alone are not sufficient. DDEB: About 70% of individuals diagnosed with DDEB are reported to have an affected parent. If a parent of a proband with DDEB is affected, the risk to the sibs is 50%. Each child of an individual with DDEB has a 50% chance of inheriting the mutation. RDEB: Each sib of an affected individual whose parents are both carriers has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal testing for pregnancies at increased risk for all subtypes of DEB is possible if the disease-causing allele(s) of an affected family member are known.
Junctional Epidermolysis Bullosa
Junctional epidermolysis bullosa (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the trachea. Blisters generally heal with no significant scarring. Broad classification of JEB includes Herlitz JEB (aka lethal) and non-Herlitz JEB (aka non-lethal).
In Herlitz JEB, the classic severe form of JEB, blisters are present at birth or become apparent in the neonatal period. Congenital malformations of the urinary tract and bladder may also occur. In non-Herlitz JEB, the phenotype may be mild with blistering localized to hands, feet, knees, and elbows with or without renal or ureteral involvement. Some individuals never blister after the newborn period. Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia, hypotrichosis, pseudosyndactyly, and other contractures.
MANAGEMENT: Treatment of manifestations: Lance and drain new blisters and dress with three layers (primary: non-adherent; secondary: for stability and protection; third: elastic properties to ensure integrity). Protect skin from shearing forces; teach caretakers proper handling of infants and children; tracheostomy if appropriate; routine dental care; appropriate footwear and physical therapy to promote/preserve ambulation; psychosocial support, including social services and psychological counseling. Prevention of secondary complications: Antiseptics to treat wound infections; attention to fluid and electrolyte balance in severely affected infants; additional nutritional support including a feeding gastrostomy when necessary; calcium, vitamin D, zinc, and iron supplements. Surveillance: Routine screening for iron-deficiency anemia, zinc deficiency, osteopenia and/or osteoporosis. Agents/circumstances to avoid: Ordinary medical tape or Band-Aids®, poorly fitting or coarse-textured clothing and footwear, activities that in general traumatize the skin (e.g., hiking, mountain biking, contact sports). Other: Consider cesarean section to reduce trauma to the skin of an affected fetus during delivery.
GENETIC COUNSELING: JEB is inherited in an autosomal recessive manner. The parents of an affected child are usually obligate heterozygotes (i.e., carriers). Because germline mosaicism and uniparental isodisomy have been reported, carrier status of parents needs to be confirmed with molecular genetic testing. At conception, each sib of an affected individual whose parents are both carriers has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. The offspring of an individual with autosomal recessive JEB are obligate heterozygotes (carriers) for a disease-causing mutation. Carrier testing for family members at increased risk and prenatal diagnosis for pregnancies at increased risk are possible if both disease-causing mutations have been identified in the family.
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