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Abnormalities of fibrillin in acquired cutis laxa
Abnormalities of fibrillin in acquired cutis laxa Mark G. Lebwohl, MD,a Elaine Schwartz, Phlz," Lloydstone Jacobs," Martin Lebwohl," Lynn Sakai, MD,b and Raul Fleischmajer, MDa New York, New York, and
Portland, Oregon Background: Degeneration of elastic tissue in acquired cutis laxa has been previously described, but microfibrils have not been adequately studied. Objective: We determined whether the microfibrillar component of elastic tissue is affected in skin of a patient with acquired cutis laxa. Methods: Lesional skin was examined with indirect immunofluorescence and immunoelectron microscopy with antibodies to fibrillin. Results: Indirect immunofluorescence showed a reduction in the distribution of fibrillinin the papillary dermis, where there was loss of the usual pattern of microfibrils perpendicular to the epidermis. Immunoelectron microscopy showed a typical distribution of elastic microfibrils around elastin of normal skin. In skin affected by cutis laxa microfibrils appeared morphologically normal but appeared less frequently in selected sites. Conclusion: The microfibrillar component of elastic fibers was reduced in the papillary dermis of this patient with acquired cutis laxa. (J AM ACAD DERMATOL 1994;30:950-4.)
Cutis laxa is a disorder of elastic tissue and is characterized by several cutaneous and visceral abnormalities. Hyperextensible skin, premature wrinkling, musculoskeletal and cardiovascular abnormalities, pulmonary emphysema, and diverticulosis of the gastrointestinal tract are a few of its many manifestations.l-' Not all of them appear in each of the various types of cutis laxa. Different inheritance patterns have been described, including several types of autosomal dominant and autosomal recessive forms, X-linked recessive inheritance, and an acquired type. I, 4-8 Histologically, skin affected by cutis laxa shows an absence or reduction of elastic tissue, but microfibrils have not been studied. I Fibrillin, a newly described glycoprotein, has been localized to 10 nm microfibrils that are present in bundles arrayed perpendicular to the dermoepidermaljunction and at the periphery of elastic fibers. 9- 11 Formation of elastic fibers results from deposition of elastin on microfibrils. Antibodies to fihril1in have From the Department of Dermatology, Mount Sinai School of Medicine, New York," and Oregon Health Sciences University, Shriners Hospital for Crippled Children, Portland.l' Accepted for publication Oct. 29, 1993. Reprint requests: Mark G. Lebwohl, MD, Box 1048, The Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029-6574. Copyright @ 1994 by the American Academy of Dermatology, Inc. 0190-9622/94 $3.00 + 0 16/1/52502
950
only recently become available for immunofluorescence examination of skin. Abnormalities of fibrillin have been demonstrated in tissue and fibroblast cultures of patients with Marfan's syndrome.l? Substantial evidence indicates that Marfan's syndrome is caused by an abnormality of the fibrillin gene. Because ofthe intimate association between fibrillin and elastic tissue, we examined lesional skin of a patient with acquired cutis laxa by indirect immunofluorescence and immunoelectron microscopy with monoclonal antibodies directed against fibrillin. CASE REPORT A 31-year-old Filipino woman had premature wrinkling of the face. At 18 years of age she noticed sagging of her earlobes. Progressive sagging and wrinkling of facial skin and, in recent years, of the neck, developed. She had no family history of cutis laxa. The patient was otherwise in good health, and her skin changes were not preceded by any illness, eruption, or antibiotic therapy. Examination revealed redundant folds of skin of the face and neck that resulted in a prematurely aged appearance (Fig. 1). A biopsy specimen showed fragmentation of dermal elastic fibers with a marked decrease in the amount of the elastin. Von Kossa stain was negative for mycobacteria and calcium. Redundant folds of skin on the neck and face were excised and stored at -80 0 C. Non-sun-exposed skin from
Journal of the American Academy of Dermatology Volume 30, Number 6
Lebwohi et ai.
951
..
~::-.:
f! t /" \:' . :~ ., .'
.
Fig. 1. Thirty-one-year-old patient with cutis laxa (left) with her 29-year-old sister. Note redundant folds of skin and prematurely aged appearance.
the hairline on the posterior of the neck was also studied. Normal breast skin obtained during a cosmetic surgical procedure from another woman was used for comparison.
MATERIAL AND METHODS Indirect immunofluorescence studies Four-micrometer sections were air dried and immersed in phosphate-buffered saline solution (PBS) for 5 minutes. They were then incubated for 45 minutes with monoclonal antifibrillin antibodies that were prepared by previously described methods." The sections were then washed with PBS and incubated for another 45 minutes with goat antimouse IgG conjugated with fluorescein. The sections were again rinsed in PBS, coverslips were mounted, and sections were examined with a Nikon microscope equipped for overhead fluorescence. To make certain that degenerated elastic tissuewas not blocking immunoreactive sites of fibrillin, some sections were predigested for 20 minutes at room temperature with 0.01% porcine pancreas elastase (Calbiochem, La Jolla, Calif.) for 20 minutes at room temperature before incubation with antibodies.
Immunoelectron microscopy Tissue was immersed in PBS for 15 minutes and then incubated with the primary antibody overnight at 4 0 C. Nonspecific rabbit immunoglobulin was used as a control. The next day the sections were washed with PBS and incubated with the secondary antibody, goatantimouseIgG conjugated with 5 nm colloidal gold particles, overnight at 4 0 C. The tissue was then rinsed with PBS and immersed in 0.1 mol/I sodium cacodylate buffer, pH 7.4.
This was followed by fixing in Karnovsky's fixative for 2 hours. Tissue was then rinsed with 0.1 mol/l sodium cacodylate buffer and then postfixed with 1% osmium tetroxide. After rinsing again in 0.1 mol/I sodium cacodylate buffer, followed by rinsing with distilled water, tissue was immersed in aqueous phosphotungstic acid 1% for 1 hour, rinsed in distilled water, immersed in 2% aqueous uranyl acetate for 1 hour, rinsed again in water, and then dehydrated in 70% ethanol followed by 95% ethanol and 100% ethanol. The specimens were then washed with propylene oxide and exposed to Spurr's resin at 72 0 C overnight. Sections of 60 to 90 nm were cut with a Porterblum ST2B ultramicrotome and harvested onto 200-mesh nickel grids. Specimens were examined in a JEOL IOOCX electron microscope.
RESULTS
Results of indirect immunofluorescence with antibodies against fibrillin are shown in Fig. 2. Fig. 2, A shows a normal distribution of fibrillin in control breast skin from an unaffected person. The microfibrils in the papillary dermis extend upward perpendicularly toward the epidermis in a pattern resembling a candelabra. In contrast, skin affected by cutis laxa (Fig. 2, B) shows loss ofthe microfibrils perpendicular to the epidermis. These changes persisted even when sections were predigested with elastase. Despite a reduction of elastic fibers in cutis laxa, indirect immunofluorescence showed persistent fibrillin in the middle and deep dermis. On immunoelectron microscopy the amount of
952 Lebwohl et al.
Journal of the Americ an Academy of Dermatology June 1994
Fig. 2. A, Indirect immunofluorescence with antibodies against fibrillin in normal skin. Note candelabra pattern of microfibrils in papillary dermis. Bar = 100 ,urn. B, Indirect immunofluorescence with antibodies against fibrillin in skin affected by cutis Jaxa. Note loss of normal pattern of fibrillin distribution in papillary dermis. Bar = 100 urn.
elastic fibers in skin with cutis laxa was reduced compared with normal skin. In contrast to the elastic fibers of normal skin, which are surrounded by microfibrils (Fig. 3, A), the elastic fibers in the upper reticular dermis of skin with cutis laxa displayed a marked reduction in or absence of surrounding microfibrils in selected sites (Fig. 3, B). However, microfibrils were normal in size and shape. No . staining was seen with nonspecific rabbit immunoglobulin as a control. DISCUSSION
An X-linked form of congenital cutis laxa, more recently called Ehlers-Danlos syndrome type IX, has been attributed to a defect in lysyl oxidase
activity caused by copper deficiency/' Other suggested mechanisms for cutis laxa include an abnormality of the laminin gene resulting in absence of laminin in the skin.P increased elastase activity resulting in degradation of elastin, 14·16 and decreased production of tropoelastin by fibroblast cultures from some but not all patients with cutis laxa.!? Reduced amounts of messenger RNA for elastin have been shown and might account for the decreased production of elastin . 18 The precise cause in acquired forms of cutis laxa is not known, but in some cases it has been suggested that destruction of elastin follows an inflammatory process in the skin.7 In several patients elastolysis has followed the acute onset of fever and an eruption
Journal of the American Academy of Dermatology Volume 30, Number 6
Lebwohl et al. 953
8 Fig. 3. A, Immunoelectron microscopy with gold-taggedantibodies against fibrillin in normal skin. Note microfibrils around elasticfibers of upper reticular dermis. Bar = 100 nm. B, Immunoelectron microscopy withgold-tagged antibodiesagainst fibrillin in skin affected by cutis laxa. Note reduction of microfibrils around elastic fibers of upper reticular dermis. Bar = 100 nm.
characterized by a neutrophilic infiltrate in the dermis.l? In several other patients cutis laxa developed after bouts of febrile neutrophilic dermatosis (Sweet's syndromej.? In one patient facial edema and generalized urticaria associated with elastolysis developed after penicillin administration." The biopsy specimen showed a dermal eosinophilic infiltrate with destruction of elastic fibers. In another patient cutis laxa developed during isoniazid therapy.P An elevation of elastase has been shown in congenital cutis laxa, but this could be a secondary phenomenon resulting from a primary abnormality
or modification of elastin.l" Elevated elastase-like protease activity has been previously demonstrated in fibroblasts from lesional skin of the patient studied in this report.P To prove that the reduction in fibrillin that we observed was not caused by degenerated elastic tissue blocking immunoreactive sites of :fibrillin, sections were predigested with elastase. Our results indicate not only a disruption of the normal pattern of elastic :fibers but marked alteration in the pattern of fibrillin, particularly in the papillary dermis. This was not affected by predigestion with elastase.
954 LebwohletaL Because of the different inheritance patterns and clinical presentations of cutis laxa, several different abnormalities and causes in this group of disorders would be expected. Thus it is not surprising that ultrastructural studies have not previously noted the abnormalities of microfibrils that we report. In one previous study at least some microfibrils were found to be normal, although many loosely bound microfibrils were also noted." Ultrastructurally normal elastic tissue components were noted in an autosomal dominant family with cutis laxa.' In an autosomal recessive form of cutis laxa an increase in microfibrils was detected by electron microscopy.P Variability in the association between microfibrils and elastin was noted in some congenital forms of cutis laxa, but the extent of variability and more specific details about this observation were not described. Absence of microfibrils around "abnormal elastin lumps" was reported in another patient with congenital cutis laxa. No normal elastic fibers were seen, but bundles of microfibrils perpendicular to the epidermis were described.P Immunofluorescence examination of cutis laxa tissue with antibodies against fibrillin has not been previously reported because these antibodies only recently became available. Because patients with acquired cutis laxa are born with skin that appears normal and cutaneous abnormalities develop after childhood, it is unlikely that a primary abnormality of fibrillin is present. More likely the destructive processes that result in degradation of elastin also affect fibrillin in these patients. This is supported by our observation of microfibrils that ultrastructurally appear normal in size and shape.
REFERENCES I. DamkierA, BrandrupF, Starklint H. Cutislaxaautosomal dominant inheritance in five generations. Clin Genet 1991;39:321-9. 2. Muster AJ, Bharati S, Herman JJ, et al. Fatal cardiovascular disease and cutislaxa following acute febrile neutrophilicdermatosis. Pediatrics 1983;102:243-8. 3. Agha A, Sakati NO, Higginbottom MC, et aI.Two forms ofcutislaxa presenting in the newborn period. Acta Paediatr Scand 1978;67:775-80. 4. Ogur G, Yuksel-Apak M, Demiryont M. Syndrome of congenital cutis laxa with ligamentous laxity and delayed development: report of a brother and sister from Turkey. Am J Med Genet 1990;37:6-9. 5. Allanson J. AustinW, Hecht F. Congenital cutislaxa with retardation of growth and motor development: a recessive disorder of connective tissue withmalelethality. Clin Genet 1986;29:133-6. 6. ByersPH, SiegelRC, Holbrook KA, et al. X-linked cutis
Journal of the American Academy of Dermatology June 1994
laxa defective cross-link formation in collagen due to decreased Iysyl oxidase activity. N Engl J Med 1980; 303:61-5. 7. LewisPG, Hood AF, Barnett NK, et al. Postinflammatory eJastolysis and cutis 1axa. J AM ACAD DERMATOL 1990; 22:40-8. 8. Ked H, Burg G, Hashimoto K. Fatal, penicillin-induced, generalized, postinflamrnatory elasto1ysis cutis 1axa. Am J DermatopathoI1983;5:267-76. 9. Sakai LY, Keene DR, EngvallE. Fibrillin, a new 350-kD glycoprotein, is a component of extracellularmicrofibrils. J Cell Bioi 1986;103:2499-509. 10. Sakai LY, KeeneDR, Glanville RW, et al. Purification and partial characterization of fibrillin, a cysteine-rich structural component of connective tissue microfibrils. J BioI Chem 1991;266:14763-70. 11. Dahlback K, LjungquistA, Lofberg H, et al. Fibrillinimmunoreactive fibers constitutea unique networkin the human dermis: immunohistochemical comparison of the distributionof fibrillin, vitronectin, amyloidP component, and orcein stainable structures in normal skin and elastosis. J Invest Dermatol 1990;94:284-91. 12. HollisterDW, GodfreyM, Sakai LY, et al. Immunohistologicabnormalities of the microfibrillar-fiber systemin the Marfan syndrome. N Engl J Med 1990;323:152-9. 13. BonneauD, Huret JL, Godeau G, et al. Recurrent ctb(7) (g31.3) and possible laminininvolvement in a neonatal cutis 1axa with a Marfan phenotype. Hum Genet 1991; 87:317-9. 14. TsujiA, Yanai J, Miura T, et al. Vascularabnormalitiesin congenital cutislaxa:reportoftwo cases. Acta Paediatr Jpn 1990;32:155-61. 15. Schwartz E, CruickshankFA, LebwohlMG. Elastase-like protease and elasto1ytic activities expressed in cultured dermal fibroblasts derived from lesional skin of patients with pseudoxanthoma elasticum, actinic elastosis, and cutis laxa. Clio Chim Acta 1988;176:219-24. 16. Anderson LL, OikarinenAI, Ryhanen L, et al. Characterization and partial purification of a neutral proteasefrom the serumof a patient withautosomalrecessive pulmonary emphysema and cutislaxa. J Lab Clio Med 1985;105:53746. 17. Sephe1 GC, ByersPH, HolbrookKA, et al. Heterogeneity of elastinexpression in cutis laxafibroblaststrains. J Invest DermatoJ 1989;93:147-53. 18. Olsen DR, Fazio MJ, Shamban AT, et al. Cutis laxa reducedelastingeneexpression inskinfibroblast culturesas determined by hybridizations with a homologous cDNA and an exon I-specific oligonucleotide. J Biol Chem 1988; 263:6465-7. 19. Christensen CC, Gonzalez-Crussi F. Postinflammatory elastolysis and cutis laxa: report of a case with aortitis.Pediatr Pathol1983;1:199-21O. 20. Koch SE, Williams ML. Acquired cutis laxa: case report and review of disorders of elasto1ysis. Pediatr Dermatol 1985;2:282-8. 21. Nanko H, Jepsen LV, Zachariae H, et al. Acquired cutis 1axa (generalized elasto1ysis): light and electron microscopic studies. Acta DermVenereal (Stockh) 1979;59:31524. 22. Kitano Y, Nishida K, Okada N, et al. Cutis Jaxa with ultrastructural abnormalities of elastic fiber. J AM ACAD DERMATOL 1989;21:378-80. 23. Van MaldergemL, VamosE, LiebaersI, et al. Severecongenital cutis laxa with pulmonary emphysema: a family with three affectedsibs.Am J Med Genet 1988;31:455-64.
Portland, Oregon Background: Degeneration of elastic tissue in acquired cutis laxa has been previously described, but microfibrils have not been adequately studied. Objective: We determined whether the microfibrillar component of elastic tissue is affected in skin of a patient with acquired cutis laxa. Methods: Lesional skin was examined with indirect immunofluorescence and immunoelectron microscopy with antibodies to fibrillin. Results: Indirect immunofluorescence showed a reduction in the distribution of fibrillinin the papillary dermis, where there was loss of the usual pattern of microfibrils perpendicular to the epidermis. Immunoelectron microscopy showed a typical distribution of elastic microfibrils around elastin of normal skin. In skin affected by cutis laxa microfibrils appeared morphologically normal but appeared less frequently in selected sites. Conclusion: The microfibrillar component of elastic fibers was reduced in the papillary dermis of this patient with acquired cutis laxa. (J AM ACAD DERMATOL 1994;30:950-4.)
Cutis laxa is a disorder of elastic tissue and is characterized by several cutaneous and visceral abnormalities. Hyperextensible skin, premature wrinkling, musculoskeletal and cardiovascular abnormalities, pulmonary emphysema, and diverticulosis of the gastrointestinal tract are a few of its many manifestations.l-' Not all of them appear in each of the various types of cutis laxa. Different inheritance patterns have been described, including several types of autosomal dominant and autosomal recessive forms, X-linked recessive inheritance, and an acquired type. I, 4-8 Histologically, skin affected by cutis laxa shows an absence or reduction of elastic tissue, but microfibrils have not been studied. I Fibrillin, a newly described glycoprotein, has been localized to 10 nm microfibrils that are present in bundles arrayed perpendicular to the dermoepidermaljunction and at the periphery of elastic fibers. 9- 11 Formation of elastic fibers results from deposition of elastin on microfibrils. Antibodies to fihril1in have From the Department of Dermatology, Mount Sinai School of Medicine, New York," and Oregon Health Sciences University, Shriners Hospital for Crippled Children, Portland.l' Accepted for publication Oct. 29, 1993. Reprint requests: Mark G. Lebwohl, MD, Box 1048, The Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029-6574. Copyright @ 1994 by the American Academy of Dermatology, Inc. 0190-9622/94 $3.00 + 0 16/1/52502
950
only recently become available for immunofluorescence examination of skin. Abnormalities of fibrillin have been demonstrated in tissue and fibroblast cultures of patients with Marfan's syndrome.l? Substantial evidence indicates that Marfan's syndrome is caused by an abnormality of the fibrillin gene. Because ofthe intimate association between fibrillin and elastic tissue, we examined lesional skin of a patient with acquired cutis laxa by indirect immunofluorescence and immunoelectron microscopy with monoclonal antibodies directed against fibrillin. CASE REPORT A 31-year-old Filipino woman had premature wrinkling of the face. At 18 years of age she noticed sagging of her earlobes. Progressive sagging and wrinkling of facial skin and, in recent years, of the neck, developed. She had no family history of cutis laxa. The patient was otherwise in good health, and her skin changes were not preceded by any illness, eruption, or antibiotic therapy. Examination revealed redundant folds of skin of the face and neck that resulted in a prematurely aged appearance (Fig. 1). A biopsy specimen showed fragmentation of dermal elastic fibers with a marked decrease in the amount of the elastin. Von Kossa stain was negative for mycobacteria and calcium. Redundant folds of skin on the neck and face were excised and stored at -80 0 C. Non-sun-exposed skin from
Journal of the American Academy of Dermatology Volume 30, Number 6
Lebwohi et ai.
951
..
~::-.:
f! t /" \:' . :~ ., .'
.
Fig. 1. Thirty-one-year-old patient with cutis laxa (left) with her 29-year-old sister. Note redundant folds of skin and prematurely aged appearance.
the hairline on the posterior of the neck was also studied. Normal breast skin obtained during a cosmetic surgical procedure from another woman was used for comparison.
MATERIAL AND METHODS Indirect immunofluorescence studies Four-micrometer sections were air dried and immersed in phosphate-buffered saline solution (PBS) for 5 minutes. They were then incubated for 45 minutes with monoclonal antifibrillin antibodies that were prepared by previously described methods." The sections were then washed with PBS and incubated for another 45 minutes with goat antimouse IgG conjugated with fluorescein. The sections were again rinsed in PBS, coverslips were mounted, and sections were examined with a Nikon microscope equipped for overhead fluorescence. To make certain that degenerated elastic tissuewas not blocking immunoreactive sites of fibrillin, some sections were predigested for 20 minutes at room temperature with 0.01% porcine pancreas elastase (Calbiochem, La Jolla, Calif.) for 20 minutes at room temperature before incubation with antibodies.
Immunoelectron microscopy Tissue was immersed in PBS for 15 minutes and then incubated with the primary antibody overnight at 4 0 C. Nonspecific rabbit immunoglobulin was used as a control. The next day the sections were washed with PBS and incubated with the secondary antibody, goatantimouseIgG conjugated with 5 nm colloidal gold particles, overnight at 4 0 C. The tissue was then rinsed with PBS and immersed in 0.1 mol/I sodium cacodylate buffer, pH 7.4.
This was followed by fixing in Karnovsky's fixative for 2 hours. Tissue was then rinsed with 0.1 mol/l sodium cacodylate buffer and then postfixed with 1% osmium tetroxide. After rinsing again in 0.1 mol/I sodium cacodylate buffer, followed by rinsing with distilled water, tissue was immersed in aqueous phosphotungstic acid 1% for 1 hour, rinsed in distilled water, immersed in 2% aqueous uranyl acetate for 1 hour, rinsed again in water, and then dehydrated in 70% ethanol followed by 95% ethanol and 100% ethanol. The specimens were then washed with propylene oxide and exposed to Spurr's resin at 72 0 C overnight. Sections of 60 to 90 nm were cut with a Porterblum ST2B ultramicrotome and harvested onto 200-mesh nickel grids. Specimens were examined in a JEOL IOOCX electron microscope.
RESULTS
Results of indirect immunofluorescence with antibodies against fibrillin are shown in Fig. 2. Fig. 2, A shows a normal distribution of fibrillin in control breast skin from an unaffected person. The microfibrils in the papillary dermis extend upward perpendicularly toward the epidermis in a pattern resembling a candelabra. In contrast, skin affected by cutis laxa (Fig. 2, B) shows loss ofthe microfibrils perpendicular to the epidermis. These changes persisted even when sections were predigested with elastase. Despite a reduction of elastic fibers in cutis laxa, indirect immunofluorescence showed persistent fibrillin in the middle and deep dermis. On immunoelectron microscopy the amount of
952 Lebwohl et al.
Journal of the Americ an Academy of Dermatology June 1994
Fig. 2. A, Indirect immunofluorescence with antibodies against fibrillin in normal skin. Note candelabra pattern of microfibrils in papillary dermis. Bar = 100 ,urn. B, Indirect immunofluorescence with antibodies against fibrillin in skin affected by cutis Jaxa. Note loss of normal pattern of fibrillin distribution in papillary dermis. Bar = 100 urn.
elastic fibers in skin with cutis laxa was reduced compared with normal skin. In contrast to the elastic fibers of normal skin, which are surrounded by microfibrils (Fig. 3, A), the elastic fibers in the upper reticular dermis of skin with cutis laxa displayed a marked reduction in or absence of surrounding microfibrils in selected sites (Fig. 3, B). However, microfibrils were normal in size and shape. No . staining was seen with nonspecific rabbit immunoglobulin as a control. DISCUSSION
An X-linked form of congenital cutis laxa, more recently called Ehlers-Danlos syndrome type IX, has been attributed to a defect in lysyl oxidase
activity caused by copper deficiency/' Other suggested mechanisms for cutis laxa include an abnormality of the laminin gene resulting in absence of laminin in the skin.P increased elastase activity resulting in degradation of elastin, 14·16 and decreased production of tropoelastin by fibroblast cultures from some but not all patients with cutis laxa.!? Reduced amounts of messenger RNA for elastin have been shown and might account for the decreased production of elastin . 18 The precise cause in acquired forms of cutis laxa is not known, but in some cases it has been suggested that destruction of elastin follows an inflammatory process in the skin.7 In several patients elastolysis has followed the acute onset of fever and an eruption
Journal of the American Academy of Dermatology Volume 30, Number 6
Lebwohl et al. 953
8 Fig. 3. A, Immunoelectron microscopy with gold-taggedantibodies against fibrillin in normal skin. Note microfibrils around elasticfibers of upper reticular dermis. Bar = 100 nm. B, Immunoelectron microscopy withgold-tagged antibodiesagainst fibrillin in skin affected by cutis laxa. Note reduction of microfibrils around elastic fibers of upper reticular dermis. Bar = 100 nm.
characterized by a neutrophilic infiltrate in the dermis.l? In several other patients cutis laxa developed after bouts of febrile neutrophilic dermatosis (Sweet's syndromej.? In one patient facial edema and generalized urticaria associated with elastolysis developed after penicillin administration." The biopsy specimen showed a dermal eosinophilic infiltrate with destruction of elastic fibers. In another patient cutis laxa developed during isoniazid therapy.P An elevation of elastase has been shown in congenital cutis laxa, but this could be a secondary phenomenon resulting from a primary abnormality
or modification of elastin.l" Elevated elastase-like protease activity has been previously demonstrated in fibroblasts from lesional skin of the patient studied in this report.P To prove that the reduction in fibrillin that we observed was not caused by degenerated elastic tissue blocking immunoreactive sites of :fibrillin, sections were predigested with elastase. Our results indicate not only a disruption of the normal pattern of elastic :fibers but marked alteration in the pattern of fibrillin, particularly in the papillary dermis. This was not affected by predigestion with elastase.
954 LebwohletaL Because of the different inheritance patterns and clinical presentations of cutis laxa, several different abnormalities and causes in this group of disorders would be expected. Thus it is not surprising that ultrastructural studies have not previously noted the abnormalities of microfibrils that we report. In one previous study at least some microfibrils were found to be normal, although many loosely bound microfibrils were also noted." Ultrastructurally normal elastic tissue components were noted in an autosomal dominant family with cutis laxa.' In an autosomal recessive form of cutis laxa an increase in microfibrils was detected by electron microscopy.P Variability in the association between microfibrils and elastin was noted in some congenital forms of cutis laxa, but the extent of variability and more specific details about this observation were not described. Absence of microfibrils around "abnormal elastin lumps" was reported in another patient with congenital cutis laxa. No normal elastic fibers were seen, but bundles of microfibrils perpendicular to the epidermis were described.P Immunofluorescence examination of cutis laxa tissue with antibodies against fibrillin has not been previously reported because these antibodies only recently became available. Because patients with acquired cutis laxa are born with skin that appears normal and cutaneous abnormalities develop after childhood, it is unlikely that a primary abnormality of fibrillin is present. More likely the destructive processes that result in degradation of elastin also affect fibrillin in these patients. This is supported by our observation of microfibrils that ultrastructurally appear normal in size and shape.
REFERENCES I. DamkierA, BrandrupF, Starklint H. Cutislaxaautosomal dominant inheritance in five generations. Clin Genet 1991;39:321-9. 2. Muster AJ, Bharati S, Herman JJ, et al. Fatal cardiovascular disease and cutislaxa following acute febrile neutrophilicdermatosis. Pediatrics 1983;102:243-8. 3. Agha A, Sakati NO, Higginbottom MC, et aI.Two forms ofcutislaxa presenting in the newborn period. Acta Paediatr Scand 1978;67:775-80. 4. Ogur G, Yuksel-Apak M, Demiryont M. Syndrome of congenital cutis laxa with ligamentous laxity and delayed development: report of a brother and sister from Turkey. Am J Med Genet 1990;37:6-9. 5. Allanson J. AustinW, Hecht F. Congenital cutislaxa with retardation of growth and motor development: a recessive disorder of connective tissue withmalelethality. Clin Genet 1986;29:133-6. 6. ByersPH, SiegelRC, Holbrook KA, et al. X-linked cutis
Journal of the American Academy of Dermatology June 1994
laxa defective cross-link formation in collagen due to decreased Iysyl oxidase activity. N Engl J Med 1980; 303:61-5. 7. LewisPG, Hood AF, Barnett NK, et al. Postinflammatory eJastolysis and cutis 1axa. J AM ACAD DERMATOL 1990; 22:40-8. 8. Ked H, Burg G, Hashimoto K. Fatal, penicillin-induced, generalized, postinflamrnatory elasto1ysis cutis 1axa. Am J DermatopathoI1983;5:267-76. 9. Sakai LY, Keene DR, EngvallE. Fibrillin, a new 350-kD glycoprotein, is a component of extracellularmicrofibrils. J Cell Bioi 1986;103:2499-509. 10. Sakai LY, KeeneDR, Glanville RW, et al. Purification and partial characterization of fibrillin, a cysteine-rich structural component of connective tissue microfibrils. J BioI Chem 1991;266:14763-70. 11. Dahlback K, LjungquistA, Lofberg H, et al. Fibrillinimmunoreactive fibers constitutea unique networkin the human dermis: immunohistochemical comparison of the distributionof fibrillin, vitronectin, amyloidP component, and orcein stainable structures in normal skin and elastosis. J Invest Dermatol 1990;94:284-91. 12. HollisterDW, GodfreyM, Sakai LY, et al. Immunohistologicabnormalities of the microfibrillar-fiber systemin the Marfan syndrome. N Engl J Med 1990;323:152-9. 13. BonneauD, Huret JL, Godeau G, et al. Recurrent ctb(7) (g31.3) and possible laminininvolvement in a neonatal cutis 1axa with a Marfan phenotype. Hum Genet 1991; 87:317-9. 14. TsujiA, Yanai J, Miura T, et al. Vascularabnormalitiesin congenital cutislaxa:reportoftwo cases. Acta Paediatr Jpn 1990;32:155-61. 15. Schwartz E, CruickshankFA, LebwohlMG. Elastase-like protease and elasto1ytic activities expressed in cultured dermal fibroblasts derived from lesional skin of patients with pseudoxanthoma elasticum, actinic elastosis, and cutis laxa. Clio Chim Acta 1988;176:219-24. 16. Anderson LL, OikarinenAI, Ryhanen L, et al. Characterization and partial purification of a neutral proteasefrom the serumof a patient withautosomalrecessive pulmonary emphysema and cutislaxa. J Lab Clio Med 1985;105:53746. 17. Sephe1 GC, ByersPH, HolbrookKA, et al. Heterogeneity of elastinexpression in cutis laxafibroblaststrains. J Invest DermatoJ 1989;93:147-53. 18. Olsen DR, Fazio MJ, Shamban AT, et al. Cutis laxa reducedelastingeneexpression inskinfibroblast culturesas determined by hybridizations with a homologous cDNA and an exon I-specific oligonucleotide. J Biol Chem 1988; 263:6465-7. 19. Christensen CC, Gonzalez-Crussi F. Postinflammatory elastolysis and cutis laxa: report of a case with aortitis.Pediatr Pathol1983;1:199-21O. 20. Koch SE, Williams ML. Acquired cutis laxa: case report and review of disorders of elasto1ysis. Pediatr Dermatol 1985;2:282-8. 21. Nanko H, Jepsen LV, Zachariae H, et al. Acquired cutis 1axa (generalized elasto1ysis): light and electron microscopic studies. Acta DermVenereal (Stockh) 1979;59:31524. 22. Kitano Y, Nishida K, Okada N, et al. Cutis Jaxa with ultrastructural abnormalities of elastic fiber. J AM ACAD DERMATOL 1989;21:378-80. 23. Van MaldergemL, VamosE, LiebaersI, et al. Severecongenital cutis laxa with pulmonary emphysema: a family with three affectedsibs.Am J Med Genet 1988;31:455-64.