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Background and Design: Electron microscopy of skin provides diagnostic criteria for distinguishing the simplex, junctional, and dystrophic forms of inherited epidermolysis bullosa (EB). The plane of cleavage in blister formation indicates the localization of structural weakness within the epidermis and basement membrane zone, and, together with ultrastructural changes in affected skin, these are clues to the underlying genetic bases for these disorders. Skin biopsy specimens from individuals with EB were evaluated by electron mocroscopy to identify structural changes and determine the subtype of EB. Results: Discrete, circumscribed clumps of keratin filaments present in the basal keratinocytes are pathognomonic for EB simplex Dowling-Meara. These and other observations of keratin filament disruption have led to the identification of mutations in keratin genes in DowlingMeara and Koebner forms of EB simplex. Changes in the density and structure of anchoring fibrils and the relative amount of type VII collagen detected by immunostaining of the dermoepidermal junction in dystrophic EB have led to sequencing of mutations in the type VII collagen gene. Although mutations in junctional EB have not been reported, findings of structural alterations in hemidesmosomes and immunohistochemical studies of kalinin (BM600 and epiligrin), and in junctional EB with pyloric atresia alterations in the integrin α6β4, indicate molecules involved in basal keratinocyte adhesion to the basement membrane that are candidate genes for junctional EB. Conclusions: Electron microscopy of skin when correlated with mutations in EB will help us understand the significance of these structural molecules in normal skin and the pathogenesis of EB.

Background: Understanding normal skin development and identifying markers of genetic skin disease expressed in postnatal skin have permitted the prenatal diagnosis of many severe genodermatoses: bullous diseases, keratinization diseases, pigment cell disorders, and disorders of the epidermal appendages (ectodermal dysplasias). Samples of 16 to 22 weeks' gestation fetal skin obtained by ultrasound-guided biopsy are evaluated using morphologic, immunohistochemical, and biochemical methods. Observations: The 12-year experience in evaluating samples from fetuses at risk of these disorders has allowed us to establish conditions that must be met before the samples are taken and the criteria for recognizing the disorder, to recommend the site(s) for sampling, and to be mindful of pitfalls that may be encountered in interpreting the tissue structure. Conclusions: Fetal skin biopsy is an important diagnostic tool that has permitted families in which members carry the abnormal gene for one of these severe skin diseases to undertake a pregnancy knowing that the condition of the fetus can be determined. Nonetheless, the ultimate goal is phase out this procedure when linkage of more of these disorders to specific genes is understood, specific mutations are characterized, and probes are available for molecular diagnoses using tissue obtained at earlier fetal ages. Until this is possible, fetal skin biopsy remains an important tool that can be used with reasonably high levels of safety and confidence. ( Arch Dermatol. 1993;129:1437-1454)

Background: Dermatosparaxis is an autosomal recessive connective tissue disorder in animals that is caused by abnormal processing of type I procollagen and results in skin laxity and fragility. Only three humans with characteristic biochemical and electronmicroscopic findings have been recognized to date. Observations: We describe the clinical and electron-microscopic findings in an affected boy who presented at birth with large full-thickness groin fissures, micrognathia, large fontanelles, umbilical hernia, and dental laminal cysts. He subsequently exhibited marked skin fragility, blue sclerae, joint laxity, increased bruisability, and growth retardation. The diagnosis of dermatosparaxis was made by electron-microscopic findings consisting of characteristic small, irregular, and circular collagen fibers in the skin. His phenotype is strikingly similar to two other reported children with the disorder, which is now classified in humans as Ehlers-Danlos VII-C. Conclusions: The newly recognized phenotype of Ehlers-Danlos VII-C is a distinct connective tissue disorder characterized by marked skin fragility and laxity, blue sclerae, increased bruisability, micrognathia, umbilical hernia, and growth retardation. A suspected clinical diagnosis can be confirmed by electron-microscopic and biochemical studies of connective tissue. ( Arch Dermatol. 1993;129:1310-1315)