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Ocular Involvement in Letterer-Siwe Disease
OCULAR I N V O L V E M E N T I N L E T T E R E R - S I W E D I S E A S E DAVID MITTELMAN, M.D., DAVID J. APPLE, M.D., AND MORTON F. GOLDBERG, M.D.
Chicago, Illinois Letterer-Siwe disease is a rare, rapidly progressive, systemic disorder of unknown etiology, which affects infants and young children. Clinically, it is characterized by skin rash, fever, anemia, hepatosplenomegaly, and lymphadenopathy. On pathologic examination, there is invasion of the spleen, liver, bone marrow, skin, skeleton, and lungs by proliferating histiocytes and eosinophils. Lichtenstein 1 feels that Letterer-Siwe dis ease is not a distinct clinicopathologic entity, but rather represents a variant of a general ized syndrome he terms histiocytosis X. This syndrome encompasses a broad spectrum of clinical disease, ranging from the localized, relatively benign eosinophilic granuloma of bone to the acute, frequently fatal LettererSiwe disease. Hand-Schiiller-Christian dis ease, characterized by a chronic course and widespread skeletal dissemination, is felt to be an intermediate form of the histiocytosis X syndrome. Orbital invasion leading to exophthalmos and papilledema, and intracranial involve ment causing cranial nerve palsies and nys tagmus are well known ophthalmic manifes tations of histiocytosis X. 2 Recently, we had the opportunity of observing an unusual clinical situation in which Letterer-Siwe dis ease played a prominent role in the cases of two unrelated patients. CASE REPORT
A 17-year-old girl was first examined at the University of Illinois Eye and Ear Infirmary on November I, 1971. The patient had been well until five months of age, when she developed a purpuric eczematoid skin rash, fever, anemia, and hepatosplenomegaly. Lymph node and skin biopsies showed extensive infiltration by large histiocytic cells with irregularly shaped vesicular nuclei and abundant pale eosinophilic cytoplasm. Scattered lymphocytes and eosinophils were also present in the infiltrate Reprint requests to David Mittelman, M.D., Uni versity of Illinois Eye and Ear Infirmary, 1855 West Taylor Street, Chicago, Illinois 60612.
(Fig. 1). A diagnosis of Letterer-Siwe disease was made. She suffered various infections during the course of her illness, including bilateral perforating corneal ulcers. Following a course of systemic corticosteroid therapy, complete remission of the dis ease was achieved by the time she was 18 months old. When we examined her initially, her right eye had no light perception, there was light perception with excellent projection in the left eye, and pendular nystagmus was present bilaterally. The corneas (Fig. 2), which were pearly white and vascularized, pre vented visualization of any intraocular detail. Ultrasonography disclosed an axial length of 24 mm in the right eye and 23 mm in the left, and showed no ab normalities in the posterior segments of either eye. There was no electroretinographic (ERG) response in the right eye and the ERG was normal in the left. On November 9, 1971, a 7.5 mm penetrating keratoplasty was performed in the left eye. The iris was totally adherent to the internal corneal surface and was exised with the host cornea. Examination of the lens revealed a dense posterior subcapsular cataract, which was extracted along with 2 ml of liquid vitreous. Histologie examination (Fig. 3) of the corneal button disclosed bullous keratopathy, fibrovascular pannus with focal absence of Bow man's layer, advanced scarring and vascularization of the corneal stroma, absence of Descemet's mem brane and endothelium, and total adherence of iris to cornea, with iris atrophy and chronic iritis. There was no evidence of Letterer-Siwe disease. Ironically, the donor cornea had been removed from the right eye of a three-year-old boy who died with advanced disseminated histiocytosis X, marked by skin rash, lytic bone lesions, anemia, hepatosplenomegaly, and lymphadenopathy. The diagnosis of Letterer-Siwe disease was subsequently confirmed by autopsy. The left cornea was also used for an other keratoplasty, and both posterior segments were obtained for pathologic examination. The globes were normal in size for the patient's age, and no significant changes were seen on exter nal examination. Grossly, the intraocular changes, which were identical in both eyes, were confined to the peripapillary region. A yellow-grey zone of fundus discoloration was noted to extend concentrically a distance of 3 mm about each disk. In addition, the disk and peripapillary retina were moderately ele vated and swollen. On microscopic examination, the changes were confined to the optic nerve head, which was edematous, and to the peripapillary choroid and retina (Fig. 4). The choroid was increased to double its normal thickness by a massive cellular infiltrate, composed almost exclusively of histiocytes, which had replaced the choroidal vasculature and obliter ated all normal choroidal elements. These large, 261
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Fig. 1 (Mittelman, Apple, and Goldberg). Skin biopsy from recipient during acute illness (16 years prior to keratoplasty). An infiltrate composed predominantly of histiocytes is present in the upper portion of the dermis. In some areas (arrows) the inflammatory infiltrate has invaded and destroyed a portion of the epidermis leading to bulla formation (hematoxylin-eosin, χ25).
Fig. 2 (Mittelman, Apple, and Goldberg). Above: Preoperative appearance of both corneas showing pearly white opacification and vascularization. Below : Clear left cornea two months after keratoplasty. The retina could be visualized through clear media and appeared normal. Largely because of sensory amblyopia, the visual acuity was counting fingers at one foot.
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Fig. 3 (Mittelman, Apple, and Goldberg). Corneal button from recipient. Note the atrophie epithelium, bulla formation, fibrovascular pannus, and scarred, vascularized stroma. E = epithelium, B = bullae, P = pannus, S = stroma (hematoxylin-eosin, X250).
plump cells exhibited abundant foamy eosinophilic cytoplasm, large oval-shaped vesicular nuclei, and poorly visualized cell borders. Rare lymphocytes were also noted within the choroid, but no eosinophils were observed. The adjacent pigment epithe lium and Bruch's membrane were intact, and the overlying retina revealed extensive degeneration of the outer layers with loss of the photoreceptors. No cellular infiltrate was noted within the retina or op tic nerve. COMMENT
In 1958, the first report of intraocular in volvement by Letterer-Siwe disease was
Fig. 4 (Mittelman, Apple, and Goldberg). Poste rior segment of donor eye. The choroidal vasculature is obliterated and the normal choroidal elements are replaced by a massive infiltrate of foamy histiocytes which have produced a thickening of the choroid to twice normal size. The overlying retinal pigment epithelium and Bruch's membrane are intact, but there is advanced degeneration of adjacent photoreceptors. RP = retinal photoreceptors, P E = pig ment epithelium, H = histiocytes, S = sciera, (hematoxylin-eosin, χ250).
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published by Anderson, Margolis, and Lynn. 3 They demonstrated histiocytic infiltration of the posterior choroid in a 16-month-old infant who succumbed to Letterer-Siwe dis ease. Heath 4 presented a case one year later with involvement of the sciera and inner ret inal layers in one eye and choroidal involve ment in the fellow eye. In the discussion of this case, it was mentioned that Parkhill had also studied a patient showing changes of Letterer-Siwe disease in the choroid. In 1965, Zimmerman5 stated that he had "seen eyes obtained at autopsy from three cases of Letterer-Siwe dsease, and in each instance there was choroidal involvement. In only one eye from one of these three cases was the anterior uveal tract affected, and in that instance it was much less impressive than the infiltrates in the choroid." Mozziconacci and associates6 reported a girl in whom the diagnosis of Letterer-Siwe disease was made at two years of age. Bilat eral choroidal lesions were noted one year later, and at the age of 12 years, enucleation of one eye was required when severe histio cytic infiltration of the vitreous and retina led to total retinal detachment and a blind painful eye. Finally, in 1970, Rupp and Holloman7 described a patient with diffuse bilat eral posterior and anterior uveal tract in volvement by Letterer-Siwe disease, compli cated by spontaneous hyphema in one eye. There is only one other report of histopathologic examination of the eye in histiocytosis X. In this report by Laymon and Sevenants,8 it was noted on autopsy exami nation of a case of Letterer-Siwe disease that the "retina and choroid appeared nor mal, and the optic nerve showed no invasion, but foam cells were present in the surround ing connective tissue." Two similar pathologic entities, juvenile xanthogranuloma and familial erythrophagocytic lymphohistiocytosis, have ophthalmic significance. The former is a generally be nign dermatologie condition of infants and children in which yellowish-brown lesions, varying in size from papules to nodules, ap
FEBRUARY, 1973
pear on the face, scalp, or extremities. The skeletal and visceral involvement that is fun damental to histiocytosis X is lacking. Spindle-shaped histiocytes and Touton gi ant cells characterize the lesions of juvenile xanthogranuloma. It may affect the cornea, epibulbar tissues, eyelids, orbit, and iris, oc casionally leading to spontaneous anterior chamber hemorrhage and secondary glau coma.5 The retina and posterior uveal tract are almost always spared by direct invasion. Erythrophagocytic lymphohistiocytosis, originally thought to represent the occur rence of Letterer-Siwe disease in siblings, is now considered a separate and unique entity.9 Clinically similar to Letterer-Siwe disease, the histopathology of this uniformly fatal disease of infants is characterized by hyperplasia of histiocytic cells, erythrophagocytosis, and infiltration of lymphocytes and histi ocytes into almost every organ in the body. It is not surprising, then, that Peterson and Kuwabara 10 found bilateral infiltration of the choroid, retina, and vitreous in this con dition. In summary, Letterer-Siwe disease can affect the eye both by direct invasion and through secondary infection. Including our donor, the literature cites nine patients with intraocular infiltration by Letterer-Siwe dis ease and only one patient in whom this in volvement was definitely ruled out by histopathologic examination. The most frequent site for direct invasion seems to be the uvea, particularly the choroid, and in this disease of unknown etiology, it is interesting to speculate whether this involvement is the re sult of local de novo transformation or of hematogenous dissemination from some pri mary source. In view of the increasingly successful therapy of Letterer-Siwe disease11 and the potentially disastrous effects of intraocular involvement (exemplified in the patient de scribed by Mozziconacci and his associates), it is of utmost importance that thorough ophthalmologic evaluation of all patients af flicted with this malady be performed.
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LETTERER-SIWE DISEASE SUMMARY
265 REFERENCES
A one-year-old girl with Letterer-Siwe disease developed bilateral perforating corneal ulcers. She underwent penetrating keratoplasty 16 years later, utilizing a donor cor nea taken from a patient who died with Let terer-Siwe disease. Examination of the pos terior segments of the donor's eyes revealed bilateral choroidal infiltration by the histiocytic disease process. Similar intraocular involvement in Let terer-Siwe disease, predominantly in the posterior uveal tract, was reported previ ously in eight patients. Uveal involvement is also seen in two similar clinicopathologic en tities—juvenile xanthogranuloma and fa milial erythrophagocytic lymphohistiocytosis. Thus, thorough ophthalmic evaluation of all patients afflicted with Letterer-Siwe dis ease is of utmost importance.
ACKNOWLEDGMENTS
We thank Dr. William F. Hughes for referring this most interesting case to the University of Illi nois Eye and Ear Infirmary, and Dr. Vernon C. Voltz for his assistance in gathering information concerning the clinical course of the recipient dur ing the acute phase of her illness.
1. Lichtenstein, L. : Histiocytosis X : integration of eosinophilic granuloma of bone, "Letterer-Siwe disease," and "Schüller-Christian disease" as related manifestations of a single nosologie entity. Arch. Path. 56:84, 1953. 2. Walsh, F. B., and Hoyt, W. F . : Clinical Neuro-ophthalmology, 3rd ed. Baltimore, Williams and Wilkins, 1969, p. 837. 3. Anderson, B., Margolis, G., and Lynn, W. S. : Ocular lesions related to disturbances in fat metab olism. Am. J. Ophth. 45(2) : 23, 1958. 4. Heath, P. : The ocular features of a case of acute reticuloendotheliosis (Letterer-Siwe type). Tr. Am. Ophth. Soc. 57:290, 1959. 5. Zimmerman, L. E. : Ocular lesions of juvenile xanthrogranuloma : Nevoxanthoendothelioma. Tr. Am. Ophth. Otolaryng. 69:412, 1965. 6. Mozziconacci, P., Offret, G., Forest, A., Attal, C, Girard, F., Hayem, F., and Trung P. H. : Histiocytose "X" avec lesions oculaires etude anatomique. Ann. Pediat. 13:348, 1966. 7. Rupp, R. H., and Holloman, K. R. : Histiocy tosis X affecting the uveal tract. Arch. Ophth. 84: 468, 1970. 8. Laymon, C. W., and Sevenants, J. J. : Systemic reticuloendothelial granuloma: a comparison of Letterer-Siwe disease, Schüller-Christian disease, and eosinophilic granuloma. Arch. Derm. Syph. 57 : 873, 1948. 9. MacMahon, H. E., Bedziel, M., and Ellis, C. A. : Familial erythrophagocytic lymphohistiocytosis. Pediatrics 32:868, 1963. 10. Peterson, R. A., and Kuwabara, T. : Ocular manifestations of familial lymphohistiocytosis. Arch. Ophth. 79:413, 1968. 11. Pearlstone, A. D., and Flom, L.: LettererSiwe's disease. J. Ped. Ophth. 7:103, 1970.
O P H T H A L M I C MINIATURE
The writer does the most who gives his reader the most knowledge, and takes from him the least time. Sydney Smith
Chicago, Illinois Letterer-Siwe disease is a rare, rapidly progressive, systemic disorder of unknown etiology, which affects infants and young children. Clinically, it is characterized by skin rash, fever, anemia, hepatosplenomegaly, and lymphadenopathy. On pathologic examination, there is invasion of the spleen, liver, bone marrow, skin, skeleton, and lungs by proliferating histiocytes and eosinophils. Lichtenstein 1 feels that Letterer-Siwe dis ease is not a distinct clinicopathologic entity, but rather represents a variant of a general ized syndrome he terms histiocytosis X. This syndrome encompasses a broad spectrum of clinical disease, ranging from the localized, relatively benign eosinophilic granuloma of bone to the acute, frequently fatal LettererSiwe disease. Hand-Schiiller-Christian dis ease, characterized by a chronic course and widespread skeletal dissemination, is felt to be an intermediate form of the histiocytosis X syndrome. Orbital invasion leading to exophthalmos and papilledema, and intracranial involve ment causing cranial nerve palsies and nys tagmus are well known ophthalmic manifes tations of histiocytosis X. 2 Recently, we had the opportunity of observing an unusual clinical situation in which Letterer-Siwe dis ease played a prominent role in the cases of two unrelated patients. CASE REPORT
A 17-year-old girl was first examined at the University of Illinois Eye and Ear Infirmary on November I, 1971. The patient had been well until five months of age, when she developed a purpuric eczematoid skin rash, fever, anemia, and hepatosplenomegaly. Lymph node and skin biopsies showed extensive infiltration by large histiocytic cells with irregularly shaped vesicular nuclei and abundant pale eosinophilic cytoplasm. Scattered lymphocytes and eosinophils were also present in the infiltrate Reprint requests to David Mittelman, M.D., Uni versity of Illinois Eye and Ear Infirmary, 1855 West Taylor Street, Chicago, Illinois 60612.
(Fig. 1). A diagnosis of Letterer-Siwe disease was made. She suffered various infections during the course of her illness, including bilateral perforating corneal ulcers. Following a course of systemic corticosteroid therapy, complete remission of the dis ease was achieved by the time she was 18 months old. When we examined her initially, her right eye had no light perception, there was light perception with excellent projection in the left eye, and pendular nystagmus was present bilaterally. The corneas (Fig. 2), which were pearly white and vascularized, pre vented visualization of any intraocular detail. Ultrasonography disclosed an axial length of 24 mm in the right eye and 23 mm in the left, and showed no ab normalities in the posterior segments of either eye. There was no electroretinographic (ERG) response in the right eye and the ERG was normal in the left. On November 9, 1971, a 7.5 mm penetrating keratoplasty was performed in the left eye. The iris was totally adherent to the internal corneal surface and was exised with the host cornea. Examination of the lens revealed a dense posterior subcapsular cataract, which was extracted along with 2 ml of liquid vitreous. Histologie examination (Fig. 3) of the corneal button disclosed bullous keratopathy, fibrovascular pannus with focal absence of Bow man's layer, advanced scarring and vascularization of the corneal stroma, absence of Descemet's mem brane and endothelium, and total adherence of iris to cornea, with iris atrophy and chronic iritis. There was no evidence of Letterer-Siwe disease. Ironically, the donor cornea had been removed from the right eye of a three-year-old boy who died with advanced disseminated histiocytosis X, marked by skin rash, lytic bone lesions, anemia, hepatosplenomegaly, and lymphadenopathy. The diagnosis of Letterer-Siwe disease was subsequently confirmed by autopsy. The left cornea was also used for an other keratoplasty, and both posterior segments were obtained for pathologic examination. The globes were normal in size for the patient's age, and no significant changes were seen on exter nal examination. Grossly, the intraocular changes, which were identical in both eyes, were confined to the peripapillary region. A yellow-grey zone of fundus discoloration was noted to extend concentrically a distance of 3 mm about each disk. In addition, the disk and peripapillary retina were moderately ele vated and swollen. On microscopic examination, the changes were confined to the optic nerve head, which was edematous, and to the peripapillary choroid and retina (Fig. 4). The choroid was increased to double its normal thickness by a massive cellular infiltrate, composed almost exclusively of histiocytes, which had replaced the choroidal vasculature and obliter ated all normal choroidal elements. These large, 261
262
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Fig. 1 (Mittelman, Apple, and Goldberg). Skin biopsy from recipient during acute illness (16 years prior to keratoplasty). An infiltrate composed predominantly of histiocytes is present in the upper portion of the dermis. In some areas (arrows) the inflammatory infiltrate has invaded and destroyed a portion of the epidermis leading to bulla formation (hematoxylin-eosin, χ25).
Fig. 2 (Mittelman, Apple, and Goldberg). Above: Preoperative appearance of both corneas showing pearly white opacification and vascularization. Below : Clear left cornea two months after keratoplasty. The retina could be visualized through clear media and appeared normal. Largely because of sensory amblyopia, the visual acuity was counting fingers at one foot.
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Fig. 3 (Mittelman, Apple, and Goldberg). Corneal button from recipient. Note the atrophie epithelium, bulla formation, fibrovascular pannus, and scarred, vascularized stroma. E = epithelium, B = bullae, P = pannus, S = stroma (hematoxylin-eosin, X250).
plump cells exhibited abundant foamy eosinophilic cytoplasm, large oval-shaped vesicular nuclei, and poorly visualized cell borders. Rare lymphocytes were also noted within the choroid, but no eosinophils were observed. The adjacent pigment epithe lium and Bruch's membrane were intact, and the overlying retina revealed extensive degeneration of the outer layers with loss of the photoreceptors. No cellular infiltrate was noted within the retina or op tic nerve. COMMENT
In 1958, the first report of intraocular in volvement by Letterer-Siwe disease was
Fig. 4 (Mittelman, Apple, and Goldberg). Poste rior segment of donor eye. The choroidal vasculature is obliterated and the normal choroidal elements are replaced by a massive infiltrate of foamy histiocytes which have produced a thickening of the choroid to twice normal size. The overlying retinal pigment epithelium and Bruch's membrane are intact, but there is advanced degeneration of adjacent photoreceptors. RP = retinal photoreceptors, P E = pig ment epithelium, H = histiocytes, S = sciera, (hematoxylin-eosin, χ250).
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published by Anderson, Margolis, and Lynn. 3 They demonstrated histiocytic infiltration of the posterior choroid in a 16-month-old infant who succumbed to Letterer-Siwe dis ease. Heath 4 presented a case one year later with involvement of the sciera and inner ret inal layers in one eye and choroidal involve ment in the fellow eye. In the discussion of this case, it was mentioned that Parkhill had also studied a patient showing changes of Letterer-Siwe disease in the choroid. In 1965, Zimmerman5 stated that he had "seen eyes obtained at autopsy from three cases of Letterer-Siwe dsease, and in each instance there was choroidal involvement. In only one eye from one of these three cases was the anterior uveal tract affected, and in that instance it was much less impressive than the infiltrates in the choroid." Mozziconacci and associates6 reported a girl in whom the diagnosis of Letterer-Siwe disease was made at two years of age. Bilat eral choroidal lesions were noted one year later, and at the age of 12 years, enucleation of one eye was required when severe histio cytic infiltration of the vitreous and retina led to total retinal detachment and a blind painful eye. Finally, in 1970, Rupp and Holloman7 described a patient with diffuse bilat eral posterior and anterior uveal tract in volvement by Letterer-Siwe disease, compli cated by spontaneous hyphema in one eye. There is only one other report of histopathologic examination of the eye in histiocytosis X. In this report by Laymon and Sevenants,8 it was noted on autopsy exami nation of a case of Letterer-Siwe disease that the "retina and choroid appeared nor mal, and the optic nerve showed no invasion, but foam cells were present in the surround ing connective tissue." Two similar pathologic entities, juvenile xanthogranuloma and familial erythrophagocytic lymphohistiocytosis, have ophthalmic significance. The former is a generally be nign dermatologie condition of infants and children in which yellowish-brown lesions, varying in size from papules to nodules, ap
FEBRUARY, 1973
pear on the face, scalp, or extremities. The skeletal and visceral involvement that is fun damental to histiocytosis X is lacking. Spindle-shaped histiocytes and Touton gi ant cells characterize the lesions of juvenile xanthogranuloma. It may affect the cornea, epibulbar tissues, eyelids, orbit, and iris, oc casionally leading to spontaneous anterior chamber hemorrhage and secondary glau coma.5 The retina and posterior uveal tract are almost always spared by direct invasion. Erythrophagocytic lymphohistiocytosis, originally thought to represent the occur rence of Letterer-Siwe disease in siblings, is now considered a separate and unique entity.9 Clinically similar to Letterer-Siwe disease, the histopathology of this uniformly fatal disease of infants is characterized by hyperplasia of histiocytic cells, erythrophagocytosis, and infiltration of lymphocytes and histi ocytes into almost every organ in the body. It is not surprising, then, that Peterson and Kuwabara 10 found bilateral infiltration of the choroid, retina, and vitreous in this con dition. In summary, Letterer-Siwe disease can affect the eye both by direct invasion and through secondary infection. Including our donor, the literature cites nine patients with intraocular infiltration by Letterer-Siwe dis ease and only one patient in whom this in volvement was definitely ruled out by histopathologic examination. The most frequent site for direct invasion seems to be the uvea, particularly the choroid, and in this disease of unknown etiology, it is interesting to speculate whether this involvement is the re sult of local de novo transformation or of hematogenous dissemination from some pri mary source. In view of the increasingly successful therapy of Letterer-Siwe disease11 and the potentially disastrous effects of intraocular involvement (exemplified in the patient de scribed by Mozziconacci and his associates), it is of utmost importance that thorough ophthalmologic evaluation of all patients af flicted with this malady be performed.
VOL. 75, NO. 2
LETTERER-SIWE DISEASE SUMMARY
265 REFERENCES
A one-year-old girl with Letterer-Siwe disease developed bilateral perforating corneal ulcers. She underwent penetrating keratoplasty 16 years later, utilizing a donor cor nea taken from a patient who died with Let terer-Siwe disease. Examination of the pos terior segments of the donor's eyes revealed bilateral choroidal infiltration by the histiocytic disease process. Similar intraocular involvement in Let terer-Siwe disease, predominantly in the posterior uveal tract, was reported previ ously in eight patients. Uveal involvement is also seen in two similar clinicopathologic en tities—juvenile xanthogranuloma and fa milial erythrophagocytic lymphohistiocytosis. Thus, thorough ophthalmic evaluation of all patients afflicted with Letterer-Siwe dis ease is of utmost importance.
ACKNOWLEDGMENTS
We thank Dr. William F. Hughes for referring this most interesting case to the University of Illi nois Eye and Ear Infirmary, and Dr. Vernon C. Voltz for his assistance in gathering information concerning the clinical course of the recipient dur ing the acute phase of her illness.
1. Lichtenstein, L. : Histiocytosis X : integration of eosinophilic granuloma of bone, "Letterer-Siwe disease," and "Schüller-Christian disease" as related manifestations of a single nosologie entity. Arch. Path. 56:84, 1953. 2. Walsh, F. B., and Hoyt, W. F . : Clinical Neuro-ophthalmology, 3rd ed. Baltimore, Williams and Wilkins, 1969, p. 837. 3. Anderson, B., Margolis, G., and Lynn, W. S. : Ocular lesions related to disturbances in fat metab olism. Am. J. Ophth. 45(2) : 23, 1958. 4. Heath, P. : The ocular features of a case of acute reticuloendotheliosis (Letterer-Siwe type). Tr. Am. Ophth. Soc. 57:290, 1959. 5. Zimmerman, L. E. : Ocular lesions of juvenile xanthrogranuloma : Nevoxanthoendothelioma. Tr. Am. Ophth. Otolaryng. 69:412, 1965. 6. Mozziconacci, P., Offret, G., Forest, A., Attal, C, Girard, F., Hayem, F., and Trung P. H. : Histiocytose "X" avec lesions oculaires etude anatomique. Ann. Pediat. 13:348, 1966. 7. Rupp, R. H., and Holloman, K. R. : Histiocy tosis X affecting the uveal tract. Arch. Ophth. 84: 468, 1970. 8. Laymon, C. W., and Sevenants, J. J. : Systemic reticuloendothelial granuloma: a comparison of Letterer-Siwe disease, Schüller-Christian disease, and eosinophilic granuloma. Arch. Derm. Syph. 57 : 873, 1948. 9. MacMahon, H. E., Bedziel, M., and Ellis, C. A. : Familial erythrophagocytic lymphohistiocytosis. Pediatrics 32:868, 1963. 10. Peterson, R. A., and Kuwabara, T. : Ocular manifestations of familial lymphohistiocytosis. Arch. Ophth. 79:413, 1968. 11. Pearlstone, A. D., and Flom, L.: LettererSiwe's disease. J. Ped. Ophth. 7:103, 1970.
O P H T H A L M I C MINIATURE
The writer does the most who gives his reader the most knowledge, and takes from him the least time. Sydney Smith