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Background
This is a broad group of disorders which are almost all characterized by subepidermal blisters with minimal inflammation. New lesions occur with the slightest trauma with spontaneous blister formation common. The disorder has been divided along clinical-pathologic presentations based primarily upon the level of the skin separation and site of the structural defect. These three types are epidermolytic, junctional, and dermolytic. Inheritance is autosomal dominant or recessive. Overall, all of these disorder are very rare. Prenatal diagnosis can be made using fetal skin biopsy or analysis of the fetal DNA using chorionic villi or amniotic fluid cells.
OUTLINE
Epidermolytic Junctional Dermolytic Gross Appearance and Clinical Variants Histopathological Features and Variants Prognosis Treatment Commonly Used Terms Internet Links Epidermolytic (Epidermolysis bullosa simplex, Keratins 5 and 14, Nonscarring)
This has intraepidermal cleavage through the basal cell layer. If direct immunofluorescence (DIF) or immunoperoxidase is used, the base of the blister contains the bullous pemphigoid antigen, laminin, type VII collagen, and the LDA-1 antigen. Most are AD inheritance with mild clinical symptoms. The defects disrupt the assembly of the keratin intermediate filaments 5 and 14. Most are missense mutations.
TYPE CLINICAL DEFECT Generalized (Koebner) type Milder variant
Serous blisters at birth or early infancy
May involve entire body but usually on hands and feet
Worse in warmer weatherMutations in the less conserved protions Localized
(Weber-Cockayne) typeMilder variant
Blisters confined to hands and feet
Onset usually within first 2 yrs but may be delayed to adolescenceSplit is within the mid-epidermis
Mutations in the less conserved portions
EB herpetiformis
(Dowling-Meara)Frequent type
Most severe form
Blisters in first few months of life on trunk, face, and extremities, often with herpetiform appearanceCharacteristic ultrastructural clumping of keratin tonofilaments
Frequent mutation of codon 125 of keratin 14These mutations are near the conserved helix boundary motifs
Ogna type Acral sanguineous blebs with generalized bruising tendency Fischer and Gedde-Dahl type Blistering with mottled pigmentation Proc Natl Acad Sci USA 1996;93:9079-9084
Linked to KRT5:P24L mutation
Superficial type Subcorneal cleavage resembling staphylococcal scalded skin syndrome Bart type Congenital localized absence of skn May be a subset of AD dystrophic EB Junctional (Lamina lucidolytic epidermolysis bullosa, Laminin 5 defects)
These are rare variants all characterized by autosomal recessive inheritance (AR). Extracutaneous involvement may be common. The defects appear to be in laminin 5 (kalinin/nicein or BM600). These are proteins located on the anchoring filaments associated with hemidesmosomes. There are other defects in uncein (10-DEJ-1), absent in 25% of patients.
TYPE CLINICAL DEFECT EB atrophicans gravis (EB letalis, Herlitz type) Lethal variant of junctional EB
Severe generalized changes with acral accentuation
Present at birth
May have non-healing area round nape of neck and perioral region
Associations include pyloric atresia, anemia, and blepharitisHum Mol Genet 1996;5:231-237
J Invest Dermatol 1999;113:314-321Caused by autosomal recessive defects in LAMA3, LAMB3, LAMC2 encoding for the alpha3, beta3, and gamma2 subunits of laminin 5
Defects in all three polypeptide chains of laminin 5-virtually complete absence
EB atrophicans mitis (Generalized atrophic benign EB) Autosomal recessive subtype of nonlethal junctional EB
Generalized blistering of the skin and mucous membranes since birth resulting in skin atrophy, focal scarring, and pigmentary changes
Alopecia, nail dystrophy, and tooth anomalies and compound melanocytic nevi
Improvement with age
Dermatologica 1976;152:72-86
Adv Dermatol 1997;13:87-119
J Clin Invest 1995;95:1345-1352
J Invest Dermatol 1998;111:887-892Deficiency in 180kd bullous pemphigoid antigen (type XVII collagen)
Occasionally defects in laminin 5 and LAD-1
Rare localized variant with acral blistering and no hair changes associated with homozygoud missense mutations of COL17A1 allowing expression of BP180 Nat Genet 1995;11:83-86 EB atrophicans inversa Truncal blistering with acral sparing
Improvement with ageEB atrophicans localisata Onset in early childhood
Lesions on soles and pretibial areaEB junctionalis progressiva Presents with nail dystrophy followed by acral blisters
May have partial deafnessCicatricial junctional EB Onset at birth with lesions healing with scarring
Contractures and scarring of the anterior nares
Oral and laryngeal lesionsPyloric atresia-junctional EB syndrome Severe blistering at birth with pyloric atresia or duodenal atresia Most affected children die during the postnatal period from severe skin involvement
Surviving patients have milder skin changes with enamel pitting, nail dystrophy, aplasia cuts congenita, and ureterovesical junction obstruction
Br J Dermatol 1988;139:862-871
Reduced expression of integrin alpha6beta4
Epidermolysis bullosa with muscular dystrophy Once classified as variant of EB simplex
Blistering at birth or shortly after
Muscle involvement is variable randing from 2 months to 35 years of ageNail dystrophy and enamel hypoplasia
May have severe involvement of airway epithelium leading to hoarseness and respiratory complicationsExp Dermatol 1996;5:237-246
Plectin is a cytoskeletal linker protein in skin and muscle-member of the plakin family
Located in the hemidesmosomal and hemidesmosomal plaques interacting with the cytoskeletal proteins
Separation occurs at the level of the hemidesmosomal plaque
PLEC1 mutations caused by mutations within exon 32
DISEASE VARIANTS CHARACTERIZATION
Junctional epidermolysis bullosa in the Middle East: clinical and genetic studies in a series of consanguineous families.Nakano A, Lestringant GG, Paperna T, Bergman R, Gershoni R, Frossard P, Kanaan M, Meneguzzi G, Richard G, Pfendner E, Uitto J, Pulkkinen L, Sprecher E.
Department of Dermatology and Cutaneous Biology, Jefferson Medical College and Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
J Am Acad Dermatol 2002 Apr;46(4):510-6 Abstract quote BACKGROUND: Junctional epidermolysis bullosa (JEB) is a group of inherited blistering diseases characterized by epidermal-dermal separation resulting from mutations that affect the function of critical components of the basement membrane zone. This group of autosomal recessive diseases is especially prevalent in regions where consanguinity is common, such as the Middle East. However, the clinical and genetic epidemiology of JEB in this region remains largely unexplored.
OBJECTIVE: The aim of the present study was to assess a series of consanguineous JEB families originating from the Middle East.
METHODS: We identified 7 families referred to us between 1998 and 1999 and originating from the United Arab Emirates, Saudi Arabia, Sudan, Yemen, and Israel. Histologic, immunofluorescence, and electron microscopy studies were performed to direct the subsequent molecular analysis. DNA obtained from all family members was amplified by means of polymerase chain reaction and analyzed by conformation-sensitive gel electrophoresis with subsequent direct sequencing.
RESULTS: In 6 families presenting with the clinical and histologic features distinctive for JEB, mutations in genes encoding 1 of the 3 subunit polypeptides of laminin-5 were identified. Two families each had mutations in LAMB3, 2 in LAMA3, and 2 in LAMC2. Out of 7 distinct mutations, 5 were novel and 2 were recurrent. No relationship was found between the presence of nonsense/frameshift mutations in laminin-5 genes and perinatal mortality, contradicting a major genotype-phenotype correlation previously reported in the European and US literature. Similarly, none of the recurrent LAMB3 hot spot mutations previously described in other populations was found in our series. Finally, in a family with the clinical diagnosis of generalized atrophic benign epidermolysis bullosa, a homozygous non-sense mutation in Col17A1 gene (encoding the BPAG2 antigen) was identified.
CONCLUSION: The present report suggests (1) the existence of a unique spectrum of mutations in the Middle East populations and (2) the need for the implementation of a diagnostic strategy tailored to the genetic features of JEB in this region.
Dermolytic (Dystrophic epidermolysis bullosa, Type VII collagen defects)
These lesions present with trauma induced blisters often followed by scarring and milia. Extracutaneous manifestations may be present. This variant is characterized by split below the lamina densa within the anchoring fibrils. Type VII collagen is markedly reduced in nearly all variants. Other membrane components which may be defective include 10-DEJ-1, KFI, AF1/AF2, 105 kd antigen, and chondroitin-6-sulfate.
TYPE CLINICAL DEFECT Dermolytic EB
(Hallopeau-Siemens)Most severe form
AR onset at birth
Large flaccid bullae disseminated
Scarring leads to digital fusion (mitten deformity)
Other mucosal surfaces involved
Sparse hair, mental retardation. dystrophic teeth
Severe (gravis) formSquamous cell carcinomas frequently develop with patients dying by 3-4th decades
Caused by mutations of the COLA71 gene Dermolytic EB, hyperplastic variant (Cockayne-Touraine) AD starting at birth
Milder blistering
Acral regions esp. extensor surfaces
May have hypertrophic scarsMatrix Biol 1999;18:29-42
Glycine substitutions in collagenous triple helical domain of the type VII collagen responsible for the dominant negative interference with wild-type protein that destabilizes trimerization of pro-alpha1 (VII) chains and disturbs anchoring fibril assembly
Dermolytic EB, albopapuloid variant (Pasini) AD starting at birth
Milder blistering
Pale papules on trunk at pubertyMatrix Biol 1999;18:29-42
Glycine substitutions in collagenous triple helical domain of the type VII collagen responsible for the dominant negative interference with wild-type protein that destabilizes trimerization of pro-alpha1 (VII) chains and disturbs anchoring fibril assembly
Cultured fibroblasts accumulate excess glycosaminoglycansPretibial EB AD developing between 11 and 24 yrs
Pale papulesSparse anchoring fibrils
Linkage to collagen VII gene COL7A1Localized dermolytic EB Onset in early childhood with some improvement with age
Prurigo nodularis-like lesions develop in variant called EB pruriginosaDermolytic EB inversa (Recessive dystrophic EB inversa) Blisters on the axilla, neck and lower part of trunk with sparing of the extremities
Mucosa commonly involvedAbsent or rudimentary anchoring fibrils Transient bullous dermolysis of the newborn AD
Self-limited course that remits within first 2 years of life and heals with mild atrophy and scarringJ Invest Dermatol 1997;109:811-814
May have delay in transport and integration of type VII collagen or excessive phagocytosis by basal keratinocytes (retention of type VII collagen) with recessive or dominant glycine substitution mutations in COL7A1 gene
Bart Syndrome Blistering accompanied with localized absence of skin and nail abnormalities J Invest Dermatol 1996;106:1340-1342
GROSS CLINICAL VARIANTS CHARACTERIZATION
Vanderbilt University School of Medicine, Nashville, Tennessee; National Epidermolysis Bullosa Registry, Nashville, Tennessee, USA
BACKGROUND: Since publication in 2000 of the Second International Consensus Report on Diagnosis and Classification of Epidermolysis Bullosa, many advances have been made to our understanding of this group of diseases, both clinically and molecularly. At the same time, new epidermolysis bullosa (EB) subtypes have been described and similarities with some other diseases have been identified.
OBJECTIVE: We sought to arrive at a new consensus of the classification of EB subtypes.
RESULTS: We now present a revised classification system that takes into account the new advances, as well as encompassing other inherited diseases that should also be included within the EB spectrum, based on the presence of blistering and mechanical fragility. Current recommendations are made on the use of specific diagnostic tests, with updates on the findings known to occur within each of the major EB subtypes. Electronic links are also provided to informational and laboratory resources of particular benefit to clinicians and their patients.
LIMITATIONS: As more becomes known about this disease, future modifications may be needed. The classification system has been designed with sufficient flexibility for these modifications.
CONCLUSION: This revised classification system should assist clinicians in accurately diagnosing and subclassifying patients with EB.
Relative extent of skin involvement in inherited epidermolysis bullosa (EB): Composite regional anatomic diagrams based on the findings of the National EB Registry, 1986 to 2002.
Devries DT, Johnson LB, Weiner M, Fine JD.
J Am Acad Dermatol. 2004 Apr;50(4):572-81. Abstract quote
BACKGROUND: Inherited epidermolysis bullosa (EB) encompasses 4 major types and at least 23 clinically distinctive phenotypes. Although considerable variability in cutaneous disease activity is known to exist within each, severity and anatomic distribution of skin lesions remain the major criteria used for subclassification.
OBJECTIVE: We sought to generate accurate anatomic "density" diagrams depicting the relative extent and location of skin lesions within each major EB subtype.
METHODS: Diagrams were created for each major EB type, on the basis of medical history and physical examination findings obtained from 1986 to 2002 from 3280 consecutive enrollees in the National EB Registry.
RESULTS: An anatomic diagram was created for each of the major EB subtypes, representing a prototypic composite photograph of cutaneous disease activity.
CONCLUSIONS: Marked variability exists in the extent of skin involvement within each major EB subtype. The use of these diagrams, generated from the world's largest cohort of patients with EB, should assist the clinician in more accurately subclassifying newly encountered patients.Junctional epidermolysis bullosa associated with congenital localized absence of skin, and pyloric atresia in two newborn siblings J Am Acad Dermatol 2001;44:330-5
2 premature male siblings with pyloric atresia, congenital localized absence of the skin, urinary obstruction, and EB at birth
Electron microscopic study revealed characteristic findings of EB simplex
Prenatal diagnosis of the next sibling was made by integrin B4 mutations and the electron microscopic study of the biopsy specimen after delivery confirmed junctional EB (JEB)Conclusion:
The presence of JEB and of CLAS in a newborn infant should raise the possibility of coexisting PA and ureterovesical obstruction
HISTOLOGICAL TYPES CHARACTERIZATION General MELANOCYTIC NEVI (EPIDERMOLYISIS BULLOSA NEVUS)
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University Hospital, 833 Chestnut St, Ste 704, Philadelphia, PA 19107.
BACKGROUND: Large acquired melanocytic nevi that occur in patients with epidermolysis bullosa (EB), referred to as EB nevi, may pose a diagnostic challenge because of their clinical and dermoscopic resemblance to melanoma. These unconventional melanocytic nevi have been encountered in all categories of hereditary EB, most of them in childhood. Although some of the reported cases have an alarming clinical appearance that is indistinguishable from melanoma, long-term follow-up has confirmed the benign nature of these rarely encountered melanocytic lesions. The histopathologic patterns of these nevi range from a banal congenital pattern to the problematic persistent pseudomelanoma pattern.
Observation We describe the clinical, dermoscopic, and histopathologic features of a large EB nevus in a toddler. Clinically, the lesion was markedly asymmetrical and irregularly pigmented with foci of stippled pigmentation and scarring, which easily fulfilled the ABCD criteria for melanoma. Accordingly, a false-positive score resulted when dermoscopy was performed. Histopathologically, a pattern of persistent melanocytic neoplasm was observed. In the following 18 months, dynamic changes of the lesion included near-complete disappearance of the pigment, which was replaced by scar, milia, and areas of healing ulcers.
Conclusion Epidermolysis bullosa nevi are dynamic melanocytic lesions that may simulate melanoma.Large melanocytic nevi in hereditary epidermolysis bullosa
Johann W. Bauer, etal.
J Am Acad Dermatol 2001;44:577-84 Abstract quote
Large melanocytic nevi occurring in areas of former blistering in patients with hereditary epidermolysis bullosa (EB) pose a problem to the clinician with regard to prognosis and therapy because they may show clinical and histopathologic features strikingly resembling malignant melanoma.
To investigate clinical and histologic criteria as well as the biologic behavior of these nevi, pigmented lesions of 12 patients (EB simplex, n = 1; junctional EB, n = 7; dystrophic EB, n = 4) of the Austrian EB registry were analyzed.
Clinically, the nevi are up to palm sized, are initially very dark, and may exhibit stippled pigmentation and irregular borders that outline areas of former blisters. Over time they usually lose pigment, the surface gets papillomatous, and finally they acquire a shagreen-like appearance. Histopathologically, the nevi frequently exhibit a compound congenital or persisting nevus/pseudomelanoma pattern. Despite this combination of features, no malignant transformation of the nevi has been seen by us even after 20 years of prospective surveillance.
Because nevi with these criteria do not fit in any of the known categories, we suggest the term EB nevi.
DYSKERATOSIS
Department of Dermatology, Rambam Medical Center and the Bruce Rappaport Faculty of Medicine, Technion-Israel, Institute of Technology, Haifa 31096, Israel.
BACKGROUND: Intracellular keratin aggregation and clumping is a characteristic ultrastructural feature in epidermolysis bullosa simplex (EBS)-Dowling Meara (DM) yet without histologic correlates in routinely stained specimens.
OBJECTIVE: We sought to detect histologic clues to keratin aggregation and clumping in the involved epidermis of EBS-DM.
METHODS: Four cases of EBS-DM caused by dominant keratin (KRT)5 and KRT14 mutations were studied histologically and ultrastructurally. The histologic slides of 11 additional EBS cases (9 Weber-Cockayne subtypes and two Koebner subtypes) were also reviewed histologically.
RESULTS: Intracytoplasmic aggregation and clumping of tonofilaments were observed ultrastructurally in all 4 EBS-DM cases. Intracytoplasmic eosinophilic homogenizations and inclusions (ie, dyskeratosis) in individual keratinocytes were detected histologically in 3 of the 4 EBS-DM cases, but in none of the 9 EBS-Weber-Cockayne cases or the two EBS-Koebner cases.
LIMITATIONS: This was a relatively small studied group.
CONCLUSION: The histopathological detection of dyskeratosis in individual keratinocytes may provide a valuable clue to keratin aggregation and clumping, and to the diagnosis in EBS-DM.
SPECIAL STAINS/|
IMMUNO-HISTOCHEMISTRYCHARACTERIZATION IMMUNHISTO-CHEMISTRY
From the Departments of *Dermatology; double daggerOrthopaedic Research Institute; section signAnatomical Pathology, St George Hospital, Sydney; ||Department of Epidemiology and Preventative Medicine, Monash University, Melbourne; and daggerThe University of New South Wales, Sydney, NSW, Australia.
The classification of epidermolysis bullosa (EB) into 3 main subtypes has been based on transmission electron microscopy (TEM) that is able to directly visualize and quantify specific ultrastructural features. Immunofluorescence antigenic mapping (IFM) is a technique that determines the precise level of skin cleavage by determining binding sites for a series of antibodies.
To date, no study has compared the accuracy of these two techniques in diagnosing the major types of EB. A prospective cohort of 33 patients thought to have EB on clinical grounds had TEM, IFM, and genetic testing performed. The sensitivities and specificities of TEM and IFM were calculated compared with the genetic results. Of 33 cases, 30 had a positive EB diagnosis. TEM subclassified EB into its three major forms in 24/30 cases (80%) and IFM in 29/30 cases (97%). Overall, TEM sensitivities and specificities when compared with genetic results were 71% and 81%, respectively. IFM sensitivities and specificities when compared with genetic results were 97% and 100%, respectively. If a patient tested positive for EB by IFM, the likelihood ratio of having a particular type of EB was consistently greater than 20 against the reference standard (compared with a likelihood ratio less than 10 for TEM).
Our results indicate that the diagnosis of EB is improved (sometimes substantially) by the use of IFM compared with TEM.
A comparative study of immunohistochemistry and electron microscopy used in the diagnosis of epidermolysis bullosa.Petronius D, Bergman R, Ben Izhak O, Leiba R, Sprecher E.
Am J Dermatopathol. 2003 Jun;25(3):198-203 Abstract quote Electron microscopic examination still is the gold standard for classifying epidermolysis bullosa, although it is relatively expensive, time consuming, and not readily available. Immunoreagents have been developed recently to map antigens in the basement membrane on routinely processed specimens.
The current study was performed to examine the diagnostic usefulness of immunohistochemistry, as compared with electron microscopic examination, for analyzing routine formalin-fixed paraffin-embedded sections of epidermolysis bullosa.
This study investigated 39 consecutively diagnosed cases of epidermolysis bullosa in which both electron microscopic examination and immunohistochemistry were used. In each case, three monoclonal antibodies were used to stain for laminin 1, collagen IV, and keratin.
The immunohistochemical patterns were defined as follows: epidermolysis bullosa simplex (laminin, collagen IV, or both at the dermal floor of the blister and keratin at both the dermal floor and the epidermal roof), junctional epidermolysis bullosa (laminin, collagen IV, or both at the dermal floor of the blister and keratin only at the epidermal roof), and dystrophic epidermolysis bullosa (collagen IV, laminin, or both, and keratin all at the epidermal roof). Altogether, electron microscopic examination subclassified epidermolysis bullosa into its three major forms in 37 of the 39 cases (95%), and immunohistochemistry in 33 of the 39 cases (85%).
All of the classifiable cases were concordant. Specifically, immunohistochemistry was diagnostic in 10 of 14 (71%) epidermolysis bullosa simplex cases, 14 of 14 (100%) junctional epidermolysis bullosa cases, and 9 of 11 (82%) dystrophic epidermolysis bullosa cases. The most frequent cause for inconclusive immunohistochemical results was failure in staining of the basement membrane with the antibodies to both laminin and collagen IV.
In conclusion, the use of immunohistochemistry on routinely processed specimens may be useful for subclassifying epidermolysis bullosa into its major forms in the majority of the cases, although it still cannot fully replace electron microscopic examination or immunofluorescence mapping in the diagnosis of epidermolysis bullosa.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS MALIGNANCIES
National Epidermolysis Bullosa Registry, Nashville, Tennessee, USA.
BACKGROUND: Case series have demonstrated that potentially lethal cutaneous squamous cell carcinomas arise in patients with recessive dystrophic epidermolysis bullosa (RDEB), although the magnitude of this risk is undefined.
METHODS: Systematic case finding and data collection were performed throughout the continental United States (1986-2002) by the National EB Registry on 3280 EB patients to determine cumulative and conditional risks for squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and malignant melanoma (MM) within each major EB subtype, as well as the cumulative risk of death from each tumor. Study design was cross-sectional, with a nested randomly sampled longitudinal subcohort (N = 450).
RESULTS: SCCs arose primarily in RDEB, especially the Hallopeau-Siemens subtype (RDEB-HS), first beginning in adolescence. Less frequently, SCCs occurred in junctional EB (JEB). Cumulative risks rose steeply in RDEB-HS, from 7.5% by age 20 to 67.8%, 80.2%, and 90.1% by ages 35, 45, and 55, respectively. In Herlitz JEB, the risk was 18.2% by age 25. SCC deaths occurred only in RDEB, with cumulative risks in RDEB-HS of 38.7%, 70.0%, and 78.7% by ages 35, 45, and 55, respectively. MM arose in RDEB-HS, with a cumulative risk of 2.5% by age 12. BCCs arose almost exclusively in the most severe EB simplex subtype (Dowling-Meara) (cumulative risk = 43.6% by age 55).
LIMITATIONS: Mutational analyses were performed on only a minority of enrollees in the National EB Registry, preventing evaluation of the possible influence of specific genotypes on the risk of developing or dying from cutaneous SCCs.
CONCLUSIONS: SCC is the most serious complication of EB within adults, especially those with RDEB-HS. By mid-adulthood, nearly all will have had at least one SCC, and nearly 80% will have died of metastatic SCC despite aggressive surgical resection. When compared with SCCs arising within the normal population, the remarkably high risk of occurrence of and then death from SCCs among RDEB patients suggests likely differences in pathogenesis. Additional studies of EB-derived tumors and SCC cell lines may not only provide new insights into the mechanisms of carcinogenesis but also means whereby these particular tumors may be prevented or more effectively treated.TREATMENT Corrective gene transfer Gene Ther 1998;5:1322-1332
Gene Ther 1999;6:42-47
Cell 1997;88:543-551
Successfully performed for the beta3 and gamma2 chains of laminin 5 and BP180
Restored protein expression in only 50% of keratinocytes may be sufficient for normal phenotype
GENETICALLY ENGINEERED SKIN
Graftskin therapy in epidermolysis bullosa.Fivenson DP, Scherschun L, Choucair M, Kukuruga D, Young J, Shwayder T.
Departments of Dermatology and Pathology, Henry Ford Hospital, and Organogenesis Inc.
J Am Acad Dermatol. 2003 Jun;48(6):886-92. Abstract quote BACKGROUND: Epidermolysis bullosa (EB) is a family of 23 genetic skin disorders for which treatments are mainly supportive. Graftskin is a bilayered living human skin construct characterized by a normal expression profile of all the genes reported as mutant in EB.
OBJECTIVE: The objective of this study was to evaluate the efficiency and durability of graftskin in the treatment of EB.
METHODS: A total of 9 children with EB were treated with graftskin. These include EB simplex: Dowling-Meara type (n = 2); Weber-Cockayne type (n = 1); junctional EB-Herlitz type (n = 1); and recessive dystrophic EB (n = 5). Lesions were debrided of epidermis and crusts followed by application of fenestrated graftskin under sterile conditions. Syndactyly hand release for "mitten deformity" was performed after removal of all epidermis under general anesthesia. All treatment sites were dressed with a nonadherent contact layer followed by absorbent foam dressing, roll gauze, and a compression wrap covering and were left intact for 1 week. Graft take was assessed clinically at weeks 1, 2, 4, 12, and 20 to 28. Graft persistence was assessed by electron microscopy and polymerase chain reaction analysis at weeks 4 and 12, and between weeks 20 and 28 on selected cases.
RESULTS: A total of 96 sites were treated with 90% to 100% healing observed by 5 to 7 days, and many sites appearing as normal skin by 10 to 14 days. Finger and hand lesions showed 50% to 90% improvement in range of motion over baseline. Two children learned to walk after graftskin treatment of chronic plantar lesions. Two children had improvement in their chronic anemia after graftskin treatment. All patients and/or parents reported rapid pain resolution. Immunologic and genetic studies of graft persistence revealed evidence of donor DNA up to 28 weeks after graftskin application. None of the samples from female patients demonstrated Y chromosome-specific sequence when analyzed by the method of short tandem repeat.
CONCLUSION: The encouraging results reported herein support the hypothesis that graftskin is more than a simple bandage or a source of growth factors to stimulate autologous closure of EB wounds. The improved quality of life and rapid achievement of growth/development milestones we have observed makes this an exciting step forward in the care of the patient with EB.
Tissue-engineered skin (Apligraf) in the healing of patients with epidermolysis bullosa wounds.Falabella AF, Valencia IC, Eaglstein WH, Schachner LA.
VAMC Department of Dermatology, 1201 NW 16th St (165), Miami, FL 33125, USA.
Arch Dermatol. 2000 Oct;136(10):1225-30. Abstract quote
BACKGROUND: At present, wound treatment of inherited epidermolysis bullosa (EB) is only supportive.
OBJECTIVE: To determine the safety and clinical effects of tissue-engineered skin (Apligraf; Organogenesis Inc, Canton, Mass) in the healing of wounds of patients with different types of EB.
DESIGN: An open-label uncontrolled study of 15 patients with EB treated with tissue-engineered skin. Each patient received tissue-engineered skin on up to 2 wounds on each of 3 clinic visits: day 1, week 6, and week 12. They were evaluated 7 (+/- 3) days and 6 weeks after each round of treatment. A quality-of-life survey was administered during week 6.
SETTING: University of Miami, Miami, Fla.
PATIENTS: Volunteers with EB.
MAIN OUTCOME MEASURE: Safety and wound healing.
RESULTS: A total of 69 different acute wounds received tissue-engineered skin at the day-1 (24 wounds), week-6 (23 wounds), and week-12 (22 wounds) visits. Overall, 63 wounds (79%) were found healed at the day-7 visit. Of the acute wounds, 82% (51/62) were healed 6 weeks after being treated, 75% (27/36) after 12 weeks, and 79% (11/14) after 18 weeks. Nine chronic wounds were also treated. Four were healed at 6 weeks; however, 7 were still open at the last clinic visit (week 18). There were no signs of rejection or clinical infection and no adverse events related to the tissue-engineered skin. The quality of life for most patients improved after treatment. Compared with patients' recollection of wounds treated with standard dressings, healing was faster and less painful.
CONCLUSION: In this series of patients, tissue-engineered skin induced very rapid healing, was not clinically rejected, and was devoid of adverse effects. It was felt by the patients and families to be more effective than conventional dressings for EB wounds.
The use of tissue-engineered skin (Apligraf) to treat a newborn with epidermolysis bullosa.Falabella AF, Schachner LA, Valencia IC, Eaglstein WH.
Department of Dermatology, University of Miami School of Medicine, Fla, USA.
Arch Dermatol. 1999 Oct;135(10):1219-22 Abstract quote BACKGROUND: Inherited epidermolysis bullosa (EB) is a mechanobullous disorder. The Dowling-Meara variant, a subtype of EB, is characterized by widespread blister formation that may include the oral cavity and nails. Many patients with the Dowling-Meara phenotype are at increased risk of sepsis and death during infancy. The treatment of EB is generally supportive. The tissue-engineered skin used (Apligraf) is a bilayered human skin equivalent developed from foreskin. It is the only Food and Drug Administration-approved skin equivalent of its kind. It is approved for the treatment of venous ulcers of the lower extremities. It has also been used to treat acute wounds, such as graft donor sites and cancer excision sites.
OBSERVATION: To our knowledge, we describe the first case in which a newborn with EB, Dowling-Meara variant, was treated with bilayered tissue-engineered skin. The areas treated with the tissue-engineered skin healed faster than the areas treated with conventional therapy. Most of the areas treated with tissue-engineered skin have remained healed, without developing new blisters. These areas appear to be more resistant to trauma.
CONCLUSIONS: Our early success with tissue-engineered skin in this patient may have a significant impact on the future treatment of neonates with EB simplex. Future studies are needed to determine if the beneficial effects of tissue-engineered skin are reproducible in other neonates with EB simplex and in patients of all ages with different subtypes of EB.
ISOTRETINOIN
Chemoprevention of squamous cell carcinoma in recessive dystrophic epidermolysis bullosa: Results of a phase 1 trial of systemic isotretinoin.
Fine JD, Johnson LB, Weiner M, Stein A, Suchindran C.
J Am Acad Dermatol. 2004 Apr;50(4):563-71. Abstract quote
BACKGROUND: Patients with recessive dystrophic epidermolysis bullosa (RDEB) are at high risk of developing squamous cell carcinoma on or after midadolescence, and most patients die of metastatic squamous cell carcinoma within 5 years of diagnosis of their first squamous cell carcinoma.
OBJECTIVE: We sought to determine whether isotretinoin can be safely administered to patients with RDEB as a possible chemopreventive agent.
METHODS: A total of 20 patients with RDEB aged 15 years or older were treated daily for 8 months with isotretinoin (with a targeted dosage of 0.5 mg/kg/d).
RESULTS: No unusual adverse reactions were noted in this patient population. Several patients experienced reduced blistering at lower doses and increased mechanical fragility at maintenance dosage.
CONCLUSIONS: Isotretinoin, at least up to a dosage of 0.5 mg/kg/d, may be safely used in patients with RDEB. Although increased fragility may occur, patients tolerated this drug well and were receptive to its long-term use for possible chemoprevention of cancer. Whether such an effect will occur is yet to be proven.Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008
Alpha6beta4 integrin-Beta 4 integrin subunit is noncovalently bound to alpha6 subunit. Trasmembrane alpha6beta4 integrin interacts with the anchoring complex (BP180, plectin, laminin 5). Also plays a role in hemidesmosome assembly. After ligation with laminin 5, it is important for cell proliferation, differentiation, and migration.
Collagen VII-Collagen variant present in the skin basement membrane within the anchoring fibrils. COL7A1 gene encodes for the protein.
Laminin 5-Widely distributed in various epithelia. Localizes to the anchoring filaments of the lamina lucida and also within the lamina densa of the basement membrane zone.
Plectin-Cytoskeletal linker protein in skin and muscle-member of the plakin family. Located in the hemidesmosomal and hemidesmosomal plaques interacting with the cytoskeletal proteins. Separation occurs at the level of the hemidesmosomal plaque
Salt split skin assay-Normal skin incubated with 1M NaCl which separates the epidermis from dermis. The epidermal half contains the upper lamina lucida, hemidesmosomes, and BP antigen. The dermal half contains laminin 5, lamina densa, and anchoring fibrils.
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Last Updated February 11, 2009
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