- Email: [email protected]
Incontinentia Pigmenti
696
AMERICAN JOURNAL OF OPHTHALMOLOGY
December, 1990
Incontinentia Pigmenti Robert A. Catalano, M.D.
Incontinentia pigmenti, also known as BlochSulzberger syndrome, is a rare X chromosomelinked disorder characterized by a triphasic dermopathy and variable malformations of the eyes, teeth, and central nervous system. The abnormal and dominant X chromosome, responsible for changes in females, causes death in male fetuses. I See also p. 701.
The first stage of the skin lesions occurs within days of birth and consists of a linear pattern of erythema and bullae on the extremities (Fig. 1). At approximately 2 months of age the vesicular lesions are superseded by verrucous lesions that last several months (Fig. 2). The final stage of irregular, whorled, marbled pigmentation occurs a few months later (Fig. 3). This pigmentation is most pronounced on the trunk. Dental anomalies include delayed dentition and missing and cone-shaped teeth (Fig. 4). Central nervous system abnormalities include seizure disorders, microcephaly, and motor disturbances.':" Retinal findings range from avascularity in the peripheral temporal retina (Fig. 5) to fibrovascular proliferation with retinal dysplasia and cicatricial retinal detachments.v' The eyes are often asymmetrically involved, and the affected eye is often microphthalmic.' Ocular involvement occurs in approximately one third of affected individuals; if abnormalities do not appear within the first year of life the prognosis for normal vision is good." The striking similarity to the retinal changes seen in retinopathy of prematurity and familial exudative vitreoretinopathy have led several investigators to propose that the proliferative changes in incontinentia pigmenti occur in response to a hypoxic stimulus.F'" Using this analogy, several clinicians have reported attempts to treat the retinal changes in incontinentia pigmenti with a modality believed efficacious for retinopathy of prematurity.v"!' The great variability in reported success attests that the understanding of incontinentia pigmenti is far from complete. Many questions regarding the pathogenic basis of the ocular findings re-
main unanswered. To develop a pathogenic theory, I will review what is known and questioned about the disorder. The first (vesicular) stage of the skin lesions of incontinentia pigmenti is associated with massive intra epidermal and dermal macrophages and eosinophils.":" Electron microscopic studies have demonstrated phagocytosis by macrophages of dyskeratotic keratinocytes and melanocytes." The inducer of dysplasia that provokes the macrophage response is uncertain. The occurrence of eosinophilia is even more perplexing. Eosinophils have long been associated with immunologic processes and eosinophil chemotactic factors have been linked to specific types of immunologic mechanisms involved in tissue damage. Experimental data
Fig. 1 (Catalano). Stage 1, vesicular dermopathy of incontinentia pigmenti on the right leg of a 15-dayold infant.
Vol. 110, No.6
Incontinentia Pigmenti
697
Fig. 2 (Catalano). Stage 2, verrucous dermopathy on the right hand of the same infant at 2 months of age.
Fig. 3 (Catalano). Stage 3, whorled pigmentary dermopathy on the right trunk of the same infant at 6 months of age.
suggest that the eosinophil serves to constrain the immune response, which minimizes its unnecessary spread." The timing and distribution of the skin changes are also peculiar. Although skin changes typically occur within the first days of life, few children, if any, have been described with lesions present at birth. The hyperpigmented (third stage) skin lesions do not occur along skin lines arranged about nerve or vascular structures, rather they occur along skin lines predisposed to melanocytotic differentiation as noted by the propensity of nevi to develop at these sites .16 In the retina, nodular accumulations of macrophages containing melanin have also been described. Typically, retinal pigment epithelial proliferation" and foreign body giant cells" overlie these accumulations. Early retinal vascular changes are characterized by abnormal arteriovenous connections and intraretinal microvascular anomalies in the peripheral temporal retina.v' In some individuals this leads to retinal dysplasia and a proliferative retinopathy. Retinal abnormalities typically occur in infancy but progression has occasionally been observed late in childhood.v" Similar dysplastic retinal changes have been reported after fetal inoculation with bluetongue virus in sheep." after photocoagulation of the retina in chick embryos," and in humans subsequent to fetal x-irradiation." It is important to contrast these findings to the observation that injuries to mature retina lead to degeneration without signs of dysplasia." The unsolved mysteries of this disorder are many. Why do eosinophilia and foreign body giant cells proliferate? What causes the dysker-
atosis and retinal dysplasia that precipitate the macrophage response? Why are the skin changes seen only after birth, and why do they become evanescent after only a few years of life? Why is the only area of retina affected the area that is immature at birth, and why are the eyes typically so asymmetrically involved? If retinal hypoxia is the cause why do some patients have large areas of avascular retina and no retinal dysplasia or proliferation? Why do some patients manifest retinal abnormalities in late childhood, and why are the results of treatment so inconsistent? Recent findings may help unravel some of these mysteries. A review of the findings in incontinentia pigmenti suggests that the affected gene is responsible for directing cell differentiation. With this in mind, two theories on the pathogenesis of incontinentia pigmenti can be developed. One theory is that the abnormal gene codes for a nonfunctioning protein that
Fig. 4 (Catalano). Missing and cone-shaped teeth in a 3D-year-old woman with incontinentia pigmenti.
698
December, 1990
AMERICAN JOURNAL OF OPHTHALMOLOGY
Heritable chromosome Instability spontaneous event or Inducing factor Chromosome aberration
J
Abnormal geneproduct In cell membrane
J
Type II cytotoxic Inflammation
J
Fig. 5 (Catalano). Fluorescein angiogram of avascular temporal retina in the right eye of a 26-year-old woman with incontinentia pigmenti. Note the terminal arborization of vessels and the arteriovenous communications. This patient's niece had proliferative retinopathy and developed a total retinal detachment in one eye.
cannot support differentiation, hence the nonviability of hemizygous male embryos. This theory, however, does not explain the propensity of changes to occur shortly after birth and why these changes appear to incite a Type II (cytotoxic) inflammatory response. A more compelling theory may be that an abnormal heritable deoxyribonucleic acid sequence renders the gene that directs differentiation inactive and the X chromosome upon which it is located susceptible to further chromosomal aberrations. In this instance the primary abnormality would impair development of male embryos, while mosaically protected heterozygous females would remain susceptible to subsequent additional chromosomal aberrations. In support of this hypothesis, increased chromosomal breakage has been reported in several families with incontinentia pigrnenti." Although it remains controversial, several reports have also indicated a common X chromosome breakpoint.i':" A common breakpoint in a chromosome supports a heritable susceptible alteration in the DNA sequence." Spontaneous or induced chromosomal breakage may result in the production of an abnormal protein or the lack of production of a normal regulatory agent. Migeon and associates" suggested that if an altered protein is responsible it would be autonomous to the cell; that is, it is not transmitted
Reactive flbrovascular proliferation
J
Cicatrization and retinal detachment Fig. 6 (Catalano). Proposed pathogenic pathway for the development of proliferative retinopathy in incontinentia pigmenti.
between cells. A plasma membrane constituent would be expected for a cell directing the development and organization of a tissue. Completion of this theory would require that the abnormal protein in the cell membrane incites a Type II (cytotoxic) inflammatory response. This is similar to what is believed to occur in some well-recognized autoimmune diseases, such as Goodpasture's syndrome. The final piece of the puzzle would then require that the inflammatory response stimulates an abnormal vascular response. A distinctive feature of incontinentia pigmenti is macrophage activation, and it has been well demonstrated that macrophages that are properly activated can stimulate angiogenesis.P'" The severity of the vascular abnormality would be dependent on the proportion of abnormal cells in these mosaic individuals. Individuals or eyes with a high proportion of abnormal retinal pigment epithelial cells may develop a massive response with overwhelming neovascularization. The inflammatory response and attendant production of an angiogenesis factor may be minimal or easily arrested in eyes with few abnormal retinal pigment epithelial cells. H has also been shown that selection disfavors cells expressing the mutant gene in patients with incontinentia pigrnenti." Mutations at the incontinentia pigmenti locus appear det-
Vol. 110, No.6
699
Incontinentia Pigmenti
rimental to the cell's proliferation. This may explain the cessation of the retinopathy and skin changes with time. Selection against abnormal cell populations may also contribute to the variability of expression between the two eyes and between individuals. If the selection is not absolute, cell lines still responsible for differentiation remain prone to inducible and spontaneous chromosomal aberrations, hence the susceptibility of the peripheral temporal retina. Late spontaneous changes likely account for the few individuals with late manifestations of the disease. The majority of affected females, however, appear to be susceptible to a postnatal inducing factor that causes chromosomal aberration and an altered cell or cell product at birth. The nature of this inducing factor is unknown. One possibility is electromagnetic radiation, in the form of infrared, visible, or ultraviolet light. This would explain the protection afforded females in utero. The proposed pathogenic basis for the ocular findings in incontinentia pigmenti is shown in Figure 6. A similar phenomenon can be proposed for the skin changes. This admittedly elaborate theory does not fully explain why retinal changes are occasionally not seen until as late as 8 years of age in some affected females. Furthermore, the basis of electromagnetic radiation inducing chromosomal aberration is speculative. Developments in other fields of science, however, suggest a heritable chromosomal instability and an abnormal gene product in the cell membrane. The postulate of a cytotoxic inflammatory response to this abnormal gene product and the induction of a macrophage-related angiogenesis factor bridges the gap between the heritable abnormal gene and the described retinal changes. Rahi and Hungerford" have also postulated that an angiogenic factor stimulates the neovascular response. Any effort to explain the pathogenesis of incontinentia pigmenti must address the puzzling findings of eosinophilia, postnatal development of abnormality in females, and the principal involvement of incompletely differentiated retina. Incontinentia pigmenti may be caused by an abnormal DNA sequence on the X chromosome, which impairs the production of a protein needed for cell differentiation and causes death in male fetuses. A subsequent spontaneous or induced aberration of this unstable chromosome results in an autologous inflammatory disorder directed against an al-
tered gene product linked to the gene responsible for differentiation. The resultant inflammation is responsible for the majority of the skin and ocular findings of the disorder. The variability in expressivity relates to mosaicism and early selection against abnormal cell populations.
From the Department of Ophthalmology, Lions Eye Institute, Albany Medical College, Albany, New York. This study was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc. Reprint requests to Robert A. Catalano, M.D., Department of Ophthalmology, Albany Medical College, Albany, NY 12208.
References 1. Raab, E. L.: Ocular lesions in incontinentia pigmenti. ]. Pediatr. Ophthalmol. Strabismus 20:42, 1983. 2. Greenwald, M. J., and Weiss, A.: Ocular manifestations of the neurocutaneous syndromes. Pediatr. Dermatol. 2:98, 1984. 3. Watzke, R. c.. Stevens, T. S., and Carney, R. G., [r.: Retinal vascular changes of incontinentia pigmenti. Arch. Ophthalmol. 94:743, 1976. 4. Francois. ].: Incontinentia pigmenti and retinal changes. Br. J. Ophthalmol. 68:19,1984. 5. Cole, J. G., and Cole, H. G.: Incontinentia pigmenti associated with changes in the posterior chamber of the eye. Am. J. Ophthalmol. 47:321, 1959. 6. Rahi, J., and Hungerford, J. R.: Early diagnosis of the retinopathy of incontinentia pigmenti. Successful treatment by cryotherapy. Br. ]. Ophthalmol. 74:377, 1990. 7. Best, W., and Rentsch, F.: Uber das "Pseudogliom" bei der incontinentia pigmenti. Klin. Monatsbl. Augenheilkd. 164:19, 1974. 8. Brown, C. A.: Incontinentia pigmenti. The development of pseudoglioma. Br. J. Ophthalmol. 72:452,1988. 9. Nix, R. R., and Apple, D. j.: Proliferative retinopathy associated with incontinentia pigmenti. Retina 1:156, 1981. 10. Nishimura, N., Oka, Y., Takagi, I., Yamana, T., and Kitano, A.: The clinical features and treatment of retinopathy of Bloch-Sulzberger syndrome. Jpn. J. Ophthalmol. 24:310, 1980. 11. Catalano, R. A., Lopatynsky, M., and Tasman, W. S.: Treatment of proliferative retinopathy associated with incontinentia pigmenti. Am. J. Ophthalmol. 110:701, 1990. 12. Lucky, A. W.: Pigmentary abnormalities in genetic disorders. Dermatol. Clin. 6:193, 1988. 13. Findlay, G. H.: On the pathogenesis of incontinentia pigmenti. Br. J. Ophthalmol. 64:141, 1952.
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AMERICAN JOURNAL OF OPHTHALMOLOGY
14. Lever, W. F.: Histopathology of the Skin. Philadelphia, J. B. Lippincott, 1967, p. 86. 15. Beeson, P. B., and Bass, D. A.: The Eosinophil. Philadelphia, W. B. Saunders, 1977, pp. 3-4. 16. Siemens, H. W.: Die melanosis corii degenerativa eine neue pigment dermatose. Arch. Dermatol. Syphilol. 157:382, 1929. 17. Mensheha-Manhart, 0., Rodrigues, M. M., Shields, J. A., Shannon, G. M., and Mirabelli, R. P.: Retinal pigment epithelium in incontinentia pigmenti. Am. J. Ophthalmol. 79:571, 1975. 18. Zweifach, P. H.: lncontinentia pigmenti. Its association with retinal dysplasia. Am. J. Ophthalmol. 62:716, 1966. 19. Silverstein, A. M., Parshall, C. J., [r., Osburn, B. I., and Prendergast, R. A.: An experimental, virusinduced retinal dysplasia in the fetal lamb. Am. J. Ophthalmol. 72:22, 1971. 20. Jeseberg, D. 0.: Ocular malformations of chick embryo produced by photocoagulation. Invest. Ophthalmol. 1:348, 1962. 21. Reese, A. B., and Straatsma, B. R.: Retinal dysplasia. Am. J. Ophthalmol. 45:199, 1958. 22. Silverstein, A. M., Osburn, B. I., and Prendergast, R. A.: The pathogenesis of retinal dysplasia. Am. J. Ophthalmol. 72:13, 1971. 23. Roberts, W. M., Jenkins, ]. J., Moorhead, E. L., and Douglass, E. c.: Incontinentia pigmenti, a chromosomal instability syndrome, is associated with childhood malignancy. Cancer 62:2370, 1988. 24. Sefiani, A., Sinnett, D., Abel, L., Szpiro-Tapia, S., Heurtz, S., Craig, I., Fraser, N., Kruse, T. A.,
December, 1990
Frydrnan. M., Peter, M. 0., Schmutz, J. L., Gilgenkrantz, S., Mitchell, G., Frezal, J., Melancon, S., Lavergne, L., Labuda, D., and Hors-Cayla, M. c.: Linkage studies do not confirm the cytogenic location of incontinentia pigmenti on Xp 11. Hum. Genet.
80:282,1988. 25. Harris, A., Lankester, S., Haan, E., Beres, J., Hulten, M., Szollar. J., Soutter, L., and Bobrow, M.: The gene for incontinentia pigmenti. Failure of linkage studies using DNA probes to confirm cytogenic localization. Clin. Genet. 34:1, 1988. 26. Gerald, P.: Chromosomes and their disorders. In Wyngaarden, J. B., and Smith, L. H., Jr. (eds.): Cecil Textbook of Medicine. Philadelphia, W. B. Saunders, 1982, p. 21. 27. Migeon, B. R., Axelman, ]., Jan de Beur, S., Valle, D., Mitchell, G. A., and Rosenbaum, K. N.: Selection against lethal alleles in females heterozygous for incontinentia pigmenti. Am. J. Hum. Genet. 44:100, 1989. 28. Folkman, J., and Klagsbrun, M.: Angiogenic factors. Science 235:442, 1987. 29. Auerbach, R., Kubai, L., and Sidky, Y.: Angiogenesis induction by tumors, embryonic tissues and lymphocytes. Cancer Res. 36:3435, 1976. 30. Shabo, A. L., Maxwell, D. S.: Experimental immunogenic proliferative retinopathy in monkeys. Am. J. Ophthalmol. 83:471, 1977. 31. Shorb, S. R., Irvine, A. R., Kimura, S. J., and Morris, B. W.: Optic disk neovascularization associated with chronic uveitis. Am. J. Ophthalmol. 82:175, 1976.
AMERICAN JOURNAL OF OPHTHALMOLOGY
December, 1990
Incontinentia Pigmenti Robert A. Catalano, M.D.
Incontinentia pigmenti, also known as BlochSulzberger syndrome, is a rare X chromosomelinked disorder characterized by a triphasic dermopathy and variable malformations of the eyes, teeth, and central nervous system. The abnormal and dominant X chromosome, responsible for changes in females, causes death in male fetuses. I See also p. 701.
The first stage of the skin lesions occurs within days of birth and consists of a linear pattern of erythema and bullae on the extremities (Fig. 1). At approximately 2 months of age the vesicular lesions are superseded by verrucous lesions that last several months (Fig. 2). The final stage of irregular, whorled, marbled pigmentation occurs a few months later (Fig. 3). This pigmentation is most pronounced on the trunk. Dental anomalies include delayed dentition and missing and cone-shaped teeth (Fig. 4). Central nervous system abnormalities include seizure disorders, microcephaly, and motor disturbances.':" Retinal findings range from avascularity in the peripheral temporal retina (Fig. 5) to fibrovascular proliferation with retinal dysplasia and cicatricial retinal detachments.v' The eyes are often asymmetrically involved, and the affected eye is often microphthalmic.' Ocular involvement occurs in approximately one third of affected individuals; if abnormalities do not appear within the first year of life the prognosis for normal vision is good." The striking similarity to the retinal changes seen in retinopathy of prematurity and familial exudative vitreoretinopathy have led several investigators to propose that the proliferative changes in incontinentia pigmenti occur in response to a hypoxic stimulus.F'" Using this analogy, several clinicians have reported attempts to treat the retinal changes in incontinentia pigmenti with a modality believed efficacious for retinopathy of prematurity.v"!' The great variability in reported success attests that the understanding of incontinentia pigmenti is far from complete. Many questions regarding the pathogenic basis of the ocular findings re-
main unanswered. To develop a pathogenic theory, I will review what is known and questioned about the disorder. The first (vesicular) stage of the skin lesions of incontinentia pigmenti is associated with massive intra epidermal and dermal macrophages and eosinophils.":" Electron microscopic studies have demonstrated phagocytosis by macrophages of dyskeratotic keratinocytes and melanocytes." The inducer of dysplasia that provokes the macrophage response is uncertain. The occurrence of eosinophilia is even more perplexing. Eosinophils have long been associated with immunologic processes and eosinophil chemotactic factors have been linked to specific types of immunologic mechanisms involved in tissue damage. Experimental data
Fig. 1 (Catalano). Stage 1, vesicular dermopathy of incontinentia pigmenti on the right leg of a 15-dayold infant.
Vol. 110, No.6
Incontinentia Pigmenti
697
Fig. 2 (Catalano). Stage 2, verrucous dermopathy on the right hand of the same infant at 2 months of age.
Fig. 3 (Catalano). Stage 3, whorled pigmentary dermopathy on the right trunk of the same infant at 6 months of age.
suggest that the eosinophil serves to constrain the immune response, which minimizes its unnecessary spread." The timing and distribution of the skin changes are also peculiar. Although skin changes typically occur within the first days of life, few children, if any, have been described with lesions present at birth. The hyperpigmented (third stage) skin lesions do not occur along skin lines arranged about nerve or vascular structures, rather they occur along skin lines predisposed to melanocytotic differentiation as noted by the propensity of nevi to develop at these sites .16 In the retina, nodular accumulations of macrophages containing melanin have also been described. Typically, retinal pigment epithelial proliferation" and foreign body giant cells" overlie these accumulations. Early retinal vascular changes are characterized by abnormal arteriovenous connections and intraretinal microvascular anomalies in the peripheral temporal retina.v' In some individuals this leads to retinal dysplasia and a proliferative retinopathy. Retinal abnormalities typically occur in infancy but progression has occasionally been observed late in childhood.v" Similar dysplastic retinal changes have been reported after fetal inoculation with bluetongue virus in sheep." after photocoagulation of the retina in chick embryos," and in humans subsequent to fetal x-irradiation." It is important to contrast these findings to the observation that injuries to mature retina lead to degeneration without signs of dysplasia." The unsolved mysteries of this disorder are many. Why do eosinophilia and foreign body giant cells proliferate? What causes the dysker-
atosis and retinal dysplasia that precipitate the macrophage response? Why are the skin changes seen only after birth, and why do they become evanescent after only a few years of life? Why is the only area of retina affected the area that is immature at birth, and why are the eyes typically so asymmetrically involved? If retinal hypoxia is the cause why do some patients have large areas of avascular retina and no retinal dysplasia or proliferation? Why do some patients manifest retinal abnormalities in late childhood, and why are the results of treatment so inconsistent? Recent findings may help unravel some of these mysteries. A review of the findings in incontinentia pigmenti suggests that the affected gene is responsible for directing cell differentiation. With this in mind, two theories on the pathogenesis of incontinentia pigmenti can be developed. One theory is that the abnormal gene codes for a nonfunctioning protein that
Fig. 4 (Catalano). Missing and cone-shaped teeth in a 3D-year-old woman with incontinentia pigmenti.
698
December, 1990
AMERICAN JOURNAL OF OPHTHALMOLOGY
Heritable chromosome Instability spontaneous event or Inducing factor Chromosome aberration
J
Abnormal geneproduct In cell membrane
J
Type II cytotoxic Inflammation
J
Fig. 5 (Catalano). Fluorescein angiogram of avascular temporal retina in the right eye of a 26-year-old woman with incontinentia pigmenti. Note the terminal arborization of vessels and the arteriovenous communications. This patient's niece had proliferative retinopathy and developed a total retinal detachment in one eye.
cannot support differentiation, hence the nonviability of hemizygous male embryos. This theory, however, does not explain the propensity of changes to occur shortly after birth and why these changes appear to incite a Type II (cytotoxic) inflammatory response. A more compelling theory may be that an abnormal heritable deoxyribonucleic acid sequence renders the gene that directs differentiation inactive and the X chromosome upon which it is located susceptible to further chromosomal aberrations. In this instance the primary abnormality would impair development of male embryos, while mosaically protected heterozygous females would remain susceptible to subsequent additional chromosomal aberrations. In support of this hypothesis, increased chromosomal breakage has been reported in several families with incontinentia pigrnenti." Although it remains controversial, several reports have also indicated a common X chromosome breakpoint.i':" A common breakpoint in a chromosome supports a heritable susceptible alteration in the DNA sequence." Spontaneous or induced chromosomal breakage may result in the production of an abnormal protein or the lack of production of a normal regulatory agent. Migeon and associates" suggested that if an altered protein is responsible it would be autonomous to the cell; that is, it is not transmitted
Reactive flbrovascular proliferation
J
Cicatrization and retinal detachment Fig. 6 (Catalano). Proposed pathogenic pathway for the development of proliferative retinopathy in incontinentia pigmenti.
between cells. A plasma membrane constituent would be expected for a cell directing the development and organization of a tissue. Completion of this theory would require that the abnormal protein in the cell membrane incites a Type II (cytotoxic) inflammatory response. This is similar to what is believed to occur in some well-recognized autoimmune diseases, such as Goodpasture's syndrome. The final piece of the puzzle would then require that the inflammatory response stimulates an abnormal vascular response. A distinctive feature of incontinentia pigmenti is macrophage activation, and it has been well demonstrated that macrophages that are properly activated can stimulate angiogenesis.P'" The severity of the vascular abnormality would be dependent on the proportion of abnormal cells in these mosaic individuals. Individuals or eyes with a high proportion of abnormal retinal pigment epithelial cells may develop a massive response with overwhelming neovascularization. The inflammatory response and attendant production of an angiogenesis factor may be minimal or easily arrested in eyes with few abnormal retinal pigment epithelial cells. H has also been shown that selection disfavors cells expressing the mutant gene in patients with incontinentia pigrnenti." Mutations at the incontinentia pigmenti locus appear det-
Vol. 110, No.6
699
Incontinentia Pigmenti
rimental to the cell's proliferation. This may explain the cessation of the retinopathy and skin changes with time. Selection against abnormal cell populations may also contribute to the variability of expression between the two eyes and between individuals. If the selection is not absolute, cell lines still responsible for differentiation remain prone to inducible and spontaneous chromosomal aberrations, hence the susceptibility of the peripheral temporal retina. Late spontaneous changes likely account for the few individuals with late manifestations of the disease. The majority of affected females, however, appear to be susceptible to a postnatal inducing factor that causes chromosomal aberration and an altered cell or cell product at birth. The nature of this inducing factor is unknown. One possibility is electromagnetic radiation, in the form of infrared, visible, or ultraviolet light. This would explain the protection afforded females in utero. The proposed pathogenic basis for the ocular findings in incontinentia pigmenti is shown in Figure 6. A similar phenomenon can be proposed for the skin changes. This admittedly elaborate theory does not fully explain why retinal changes are occasionally not seen until as late as 8 years of age in some affected females. Furthermore, the basis of electromagnetic radiation inducing chromosomal aberration is speculative. Developments in other fields of science, however, suggest a heritable chromosomal instability and an abnormal gene product in the cell membrane. The postulate of a cytotoxic inflammatory response to this abnormal gene product and the induction of a macrophage-related angiogenesis factor bridges the gap between the heritable abnormal gene and the described retinal changes. Rahi and Hungerford" have also postulated that an angiogenic factor stimulates the neovascular response. Any effort to explain the pathogenesis of incontinentia pigmenti must address the puzzling findings of eosinophilia, postnatal development of abnormality in females, and the principal involvement of incompletely differentiated retina. Incontinentia pigmenti may be caused by an abnormal DNA sequence on the X chromosome, which impairs the production of a protein needed for cell differentiation and causes death in male fetuses. A subsequent spontaneous or induced aberration of this unstable chromosome results in an autologous inflammatory disorder directed against an al-
tered gene product linked to the gene responsible for differentiation. The resultant inflammation is responsible for the majority of the skin and ocular findings of the disorder. The variability in expressivity relates to mosaicism and early selection against abnormal cell populations.
From the Department of Ophthalmology, Lions Eye Institute, Albany Medical College, Albany, New York. This study was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc. Reprint requests to Robert A. Catalano, M.D., Department of Ophthalmology, Albany Medical College, Albany, NY 12208.
References 1. Raab, E. L.: Ocular lesions in incontinentia pigmenti. ]. Pediatr. Ophthalmol. Strabismus 20:42, 1983. 2. Greenwald, M. J., and Weiss, A.: Ocular manifestations of the neurocutaneous syndromes. Pediatr. Dermatol. 2:98, 1984. 3. Watzke, R. c.. Stevens, T. S., and Carney, R. G., [r.: Retinal vascular changes of incontinentia pigmenti. Arch. Ophthalmol. 94:743, 1976. 4. Francois. ].: Incontinentia pigmenti and retinal changes. Br. J. Ophthalmol. 68:19,1984. 5. Cole, J. G., and Cole, H. G.: Incontinentia pigmenti associated with changes in the posterior chamber of the eye. Am. J. Ophthalmol. 47:321, 1959. 6. Rahi, J., and Hungerford, J. R.: Early diagnosis of the retinopathy of incontinentia pigmenti. Successful treatment by cryotherapy. Br. ]. Ophthalmol. 74:377, 1990. 7. Best, W., and Rentsch, F.: Uber das "Pseudogliom" bei der incontinentia pigmenti. Klin. Monatsbl. Augenheilkd. 164:19, 1974. 8. Brown, C. A.: Incontinentia pigmenti. The development of pseudoglioma. Br. J. Ophthalmol. 72:452,1988. 9. Nix, R. R., and Apple, D. j.: Proliferative retinopathy associated with incontinentia pigmenti. Retina 1:156, 1981. 10. Nishimura, N., Oka, Y., Takagi, I., Yamana, T., and Kitano, A.: The clinical features and treatment of retinopathy of Bloch-Sulzberger syndrome. Jpn. J. Ophthalmol. 24:310, 1980. 11. Catalano, R. A., Lopatynsky, M., and Tasman, W. S.: Treatment of proliferative retinopathy associated with incontinentia pigmenti. Am. J. Ophthalmol. 110:701, 1990. 12. Lucky, A. W.: Pigmentary abnormalities in genetic disorders. Dermatol. Clin. 6:193, 1988. 13. Findlay, G. H.: On the pathogenesis of incontinentia pigmenti. Br. J. Ophthalmol. 64:141, 1952.
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AMERICAN JOURNAL OF OPHTHALMOLOGY
14. Lever, W. F.: Histopathology of the Skin. Philadelphia, J. B. Lippincott, 1967, p. 86. 15. Beeson, P. B., and Bass, D. A.: The Eosinophil. Philadelphia, W. B. Saunders, 1977, pp. 3-4. 16. Siemens, H. W.: Die melanosis corii degenerativa eine neue pigment dermatose. Arch. Dermatol. Syphilol. 157:382, 1929. 17. Mensheha-Manhart, 0., Rodrigues, M. M., Shields, J. A., Shannon, G. M., and Mirabelli, R. P.: Retinal pigment epithelium in incontinentia pigmenti. Am. J. Ophthalmol. 79:571, 1975. 18. Zweifach, P. H.: lncontinentia pigmenti. Its association with retinal dysplasia. Am. J. Ophthalmol. 62:716, 1966. 19. Silverstein, A. M., Parshall, C. J., [r., Osburn, B. I., and Prendergast, R. A.: An experimental, virusinduced retinal dysplasia in the fetal lamb. Am. J. Ophthalmol. 72:22, 1971. 20. Jeseberg, D. 0.: Ocular malformations of chick embryo produced by photocoagulation. Invest. Ophthalmol. 1:348, 1962. 21. Reese, A. B., and Straatsma, B. R.: Retinal dysplasia. Am. J. Ophthalmol. 45:199, 1958. 22. Silverstein, A. M., Osburn, B. I., and Prendergast, R. A.: The pathogenesis of retinal dysplasia. Am. J. Ophthalmol. 72:13, 1971. 23. Roberts, W. M., Jenkins, ]. J., Moorhead, E. L., and Douglass, E. c.: Incontinentia pigmenti, a chromosomal instability syndrome, is associated with childhood malignancy. Cancer 62:2370, 1988. 24. Sefiani, A., Sinnett, D., Abel, L., Szpiro-Tapia, S., Heurtz, S., Craig, I., Fraser, N., Kruse, T. A.,
December, 1990
Frydrnan. M., Peter, M. 0., Schmutz, J. L., Gilgenkrantz, S., Mitchell, G., Frezal, J., Melancon, S., Lavergne, L., Labuda, D., and Hors-Cayla, M. c.: Linkage studies do not confirm the cytogenic location of incontinentia pigmenti on Xp 11. Hum. Genet.
80:282,1988. 25. Harris, A., Lankester, S., Haan, E., Beres, J., Hulten, M., Szollar. J., Soutter, L., and Bobrow, M.: The gene for incontinentia pigmenti. Failure of linkage studies using DNA probes to confirm cytogenic localization. Clin. Genet. 34:1, 1988. 26. Gerald, P.: Chromosomes and their disorders. In Wyngaarden, J. B., and Smith, L. H., Jr. (eds.): Cecil Textbook of Medicine. Philadelphia, W. B. Saunders, 1982, p. 21. 27. Migeon, B. R., Axelman, ]., Jan de Beur, S., Valle, D., Mitchell, G. A., and Rosenbaum, K. N.: Selection against lethal alleles in females heterozygous for incontinentia pigmenti. Am. J. Hum. Genet. 44:100, 1989. 28. Folkman, J., and Klagsbrun, M.: Angiogenic factors. Science 235:442, 1987. 29. Auerbach, R., Kubai, L., and Sidky, Y.: Angiogenesis induction by tumors, embryonic tissues and lymphocytes. Cancer Res. 36:3435, 1976. 30. Shabo, A. L., Maxwell, D. S.: Experimental immunogenic proliferative retinopathy in monkeys. Am. J. Ophthalmol. 83:471, 1977. 31. Shorb, S. R., Irvine, A. R., Kimura, S. J., and Morris, B. W.: Optic disk neovascularization associated with chronic uveitis. Am. J. Ophthalmol. 82:175, 1976.