June 1977 The Journal o f P E D I A T R I C S
939
"'Flecked retina"--an association with primary hyperoxaluria A chiM with hyperoxaluria, probable Type L was noted to have a "flecked retina" on funduscopic examination at age 289 months," it persisted throughout his seven years of life. The relationship of the ocular findings to his metabolic disease is discussed.
Ruth P. Gottlieb, M.D.,* and Joseph A. Ritter, M.D., Philadelphia, Pa.
PRIMARY HYPEROXALURIA is an autosomal recessive inherited disorder of glyoxylate metabolism characterized by calcium oxalate deposition in m a n y organs of the body? -~ To our knowledge, no record of involvement of the eyes in patients with oxalosis is available, other than that of retinal deposition of calcium oxalate in an adult with oxalosis secondary to anesthesia with methoxyflurane.s. ~, We have observed a child with primary hyperoxaluria, probable Type I, who had retinal changes which appear similar to, but more extensive than, those described by Bullock and Albert ~ and Albert and associates?' In the latter case, deposition of calcium oxalate in the retina was confirmed. This retinal appearance, termed "flecked retina," was noted in our patient at age 2J/2 months and persisted throughout his seven years of life. Recognition of this retinal appearance may aid in early diagnosis of primary hyperoxaluria.
CASE REPORT Patient S. T., a 2,400 gm boy, was born of a 15-year-old, gravida 1, para 1, black woman after an uneventful 40-week gestation. The neonatal period was normal, but during the first two months of life he evidenced increasing lethargy which led to hospitalization at Philadelphia General Hospital at age 289 months. On admission he was febrile, dehydrated, severely anemic (hemoglobin 6.5 gm/dl), acidotic (pH 7.12), and uremic (BUN 65 mg/dl). Initial physical examination revealed poor From the Department of Pediatrics, Jefferson Medical College of Thomas Jefferson University, and the University of Pennsylvania School of Medicine. *Reprint address: Jefferson Medical College, 1025 Walnut St., Philadelphia, PA 1910Z
tissue turgor, but was otherwise unremarkable except for the ocular findings. The ocular muscle balance was normal; funduscopy revealed innumerable, discrete, white pinhead-size lesions diffusely scattered throughout the posterior pole of both eyes (Fig. 1). These lesions were within or behind the sensory retina, spared the macula, and were more dense toward the equator. There was neither vitreous haze nor retinal pigmentary changes. At 9 months of age, he was noted to have pendular ocular nystagmus, and re-examination of the fundus revealed the white punctate lesions to be unchanged, but both maculae showed fairly well-circumscribed, semitransparent, yellowish white, dome-shaped elevations. Several months later, a fluorescein fundus study revealed that the punctate retinal lesions acquired fluorescence during the choroidal phase and did not change in size or intensity with time. There was marked pooling and leaking of fluorescein in tha macular areas, which persisted throughout the 30-minute examination. When he was 4 years old, repeat funduscopic examination again revealed the multiple punctate retinal lesions, but now considerable macular scarring was present (Fig. 2). Visual acuity could not be accurately determined at this time, but the child could identify objects the size of a pen. [
Abbreviations used CMV: cytomegalovirus RPE: retinal pigment epithelium
[
At age 8 months, an open renal biopsy was performed in order to clarify the child's persistent anemia, acidosis, and uremia. The biopsied tissue contained massive intraluminal deposition of birefringent crystals arranged as radiating sheaves to form rosettes characteristic of calcium oxalate. When he was 81/2 months of age, the 24-hour urinary excretion of oxalate was 24 mg or 120 mg/1.73 M ~ (normal value ~ 55 rag/24 hour/l.73 M~). Subsequent determinations showed oxalate excretions of 98 to 288 rag/24 hr/1.73 M ~. The urine was also analyzed for
Vol. 90, No. 6, pp. 939-942
940
Gottlieb and Ritter
The Journal of Pediatrics June 1977
Fig. 1. Ocular fundus at age 25 months.
Fig. 2. Ocular fundus at age 4 years. glycolate and glycerate: the former was 40 mg/24 hour or 119 mg/24 hour/1.73 M'-', and the latter was undetectable (normal value for glycolate excretion ___60 mg/24 hour/1.73 M-'; no glycerate should be detectable). During this hospitalization, studies of urine, blood, and renal tissue for cytomegalovirus isolation were performed: all were indicative of CMV infection. At age 4 years, the child was admitted to Thomas Jefferson University Hospital because of increasing bone pain and radiographic demonstration of cystic lesions throughout the pelvis and both upper and lower extremities. A bone biopsy taken from the iliac crest showed birefringent crystalline deposits in the marrow consistent with calcium oxalate deposition.
The child was treated symptomatically with pyridoxine, magnesium oxide, alkalinizing solutions, and vitamin D; however, renal function progressively deteriorated and at age 7 years he died in uremia. A limited autopsy was performed. demonstrating progression of the renal and bone pathology. Examination of the eyes and brain was not permitted. DISCUSSION Primary hyperoxaluria is a n inherited metabolic disorder o f glyoxylate m e t a b o l i s m d u e to a deficiency o f the cytoplasmic enzyme 2-oxo-glutarate: glyoxylate carboligase (Type I) that is responsible for increased
Volume 90 Number 6
urinary excretion of oxalate and glycolate,'" or to a deficiency of D-glyceric dehydrogenase (Type II) leading to increased urinary excretion of oxalate and glycerate. '~ Although the most common presenting symptoms relate to the presence of nephrolithiasis, extrarenal deposition has been reported in bones -~ heart,: ..... male genital tract,' central nervous system, '~, ~ and in the media of large, medium, and small arteries.:' Infants with this disorder may present with symptoms of renal failure, have nephrocalcinosis without nephrolithiasis, and die in renal failure before reaching one year of age. ~ Our patient presumably had hyperoxaluria Type I as indicated by the elevated urinary excretion of oxalate and glycolate. The renal biopsy showing massive intraluminal deposition of birefringent crystals and the bone biopsy showing birefringent crystalline deposits in the marrow are characteristic pathologic findings of primary hyperoxaluria.'. '~ Death from chronic renal failure is clinically characteristic of this disorder. '~ The child's illness was initially thought to be due to CMV infection and indeed may have been complicated by it. However, the punctate retinal lesions evident at age 2V,. months, followed by retinal pigment epithelium detachment in the macular area, with subsequent macular scarring, and a fluorescein fundus study suggestive of a lesion at the level of the retinal pigment epithelium, to our knowledge, have not been described previously in cytomegalovirus inclusion disease or in primary hyperoxaluria. The usual ocular picture of acute CMV infection includes broad, widely distributed patches of yellow-white granular material representing acute retinal necrosis, extensive flame-shaped intraretinal hemorrhage, and arteriolar attenuation or sheathing as a result of necrosis of vessel walls. ':~The ocular signs of healed chorioretinitis following CMV infection are nonspecific: they include pleomorphic chorioretinal scars, which have white centers of exposed sclera bordered by dense, black rims of accumulated pigment. H. '.; Although no similar reports of calcium oxalate deposition in the retina have been located in patients with primary hyperoxaluria, Bullock and AlberP have reported the fundus changes in oxalosis secondary to methoxyflurane anesthesia. The ocular fundi in their patient were normal prior to surgery in which methoxyflurane was used for anesthesia; funduscopic examination three years later revealed numerous yellowish white punctate lesions diffusely scattered throughout the posterior poles and midperiphery of both eyes. The appearance of the optic discs, maculae, and vessels was normal. A second patient reported by Albert and colleagues" also developed similar fundus lesions following methoxyflurane anesthesia, Fluorescein angiography showed faint "window defects"
Flecked retina
94 1
corresponding to the appearance of the lesions. No late staining was seen in the area of the lesions. In the first patient, pathologic study of the eyes postmortem showed the vitreous, choroid, disc, and sclera to be normal; the retinal pigment epithelium contained extensive crystalline deposits exhibiting birefringence when examined under polarized filters. The choroid and choriocapillaris were unremarkable as were the optic nerve and sclera. Radiation diffraction and optical index studies on identical crystals removed from the kidney positively identified the crystals as calcium oxalate. Pathologic examination of the eyes of the second patient was not permitted. The authors ~ called the fundus appearance "flecked retina," a term originally applied by Krill and Klien ' ' to several conditions with a similar appearance of the fundus (fundus albipunctatus, fundus flavimaculatus, and colloid bodies or drusen). Caine and associates 'T produced a "flecked retina" in rabbits by the subcutaneous injection of dibutyl oxalate. The earliest funduscopic changes were small, pinpoint, depigmented areas of the retina apparently related to a disturbance of the pigmented epithelium. On the fourth day, discrete white flecks were observed throughout the posterior pole, and in less concentration up to the equator. On histopathologic examination, the rabbits with "flecked retinas" demonstrated intracellular needle-like crystals within numerous cells of the RPE. The crystals were identified as calcium oxalate. The ocular fundus of our patient indicates a lesion at the level of the RPE, and calcium oxalate deposits were also identified in the kidney and in bone. In view of the studies reported above, it seems likely that the retinal lesions were also due to deposits of calcium oxalate in the RPE. We would like to thank Dr. Hibbard Williams for performing the urinary oxalate, glycolate, and glycerate determinations; Dr. Grant Morrow for performing the urinary oxalate determinations: Dr. Stanley Plotkin for performing CMV studies; and Dr. David Sauer and other members of the ophthalmology departments of the University of Pennsylvania School of Medicine and Jefferson Medical College of Thomas Jefferson University for performing fundus studies and photography, and for assistance in interpretation of the fundus findings. REFERENCES
I. Williams HE, and Smith LH Jr: Disorders of oxalate metabolism, Am J Med 45:715, 1968. 2. Dunn HG: Oxalosis, Am J Dis Child 90:58, 1955. 3. Davis JS, Klingberg WG, and Stowell RE: Nephrolithiasis and nephrocalcinosis with calcium oxalate crystals in kidneys and bones, J PEDIATR36:323, 1950. 4. Aponte GE, and Fetter TR: Familial idiopathic oxalate nephrocalcinosis, Am J Clin Pathol 24:1363, 1954.
942
Gottlieb and Ritter
5, Burke EC, Baggenstoss AH, Owen CA Jr, Power MH, and Lohr OW: Oxalosis, Pediatrics 15:383, 1955. 6. Chou LY, and Donohue WL: Oxalosis-a possible inborn error of metabolism, Pediatrics 10:662, 1952. 7. Katzuni E, and Sandbank U: Oxalosis, Arch Dis Child 34:60, 1959. 8. Bullock JD, and Albert DM: Flecked retina, Arch Ophthalmol 93:26, 1975. 9. Albert DM, Bullock JD, Lahav M, and Caine R: Flecked retina secondary to oxalate crystals from methoxyflurane anesthesia: Clinical and experimental studies, Trans Am Acad Ophthalmol Otolaryngol 76:817, 1975. 10. Koch J, Stokstad ELR, Williams HE, and Smith LH Jr: Deficiency of 2-oxo-glutarate: glyoxylate carboligase activity in primary hyperoxaluria, Proc Natl Acad Sci 57:1123, 1967. 11. Williams HE, and Smith LH Jr: L-Glyceric aciduria: A new
The Journal of Pediatrics June 1977
12. 13.
14.
15. 16. 17.
genetic variant of primary oxaluria, N Engl J Med 278:233, 1968. Hockaday TDR, Clayton JE, Frederick EW, and Smith LH Jr: Primary hyperoxaluria, Medicine 43:315, 1964. Wyhinny GJ, Apple DJ, Guastella FR, and Vygantas CM: Adult cytomegalic inclusion retinitis, Am J Ophthalmol 76:773, 1973. Hoyt WF, and Beeston D: In The ocular fundus in neurologic disease, St. Louis, 1966, The CV Mosby Company, p 98. Boniuk I: In International ophthalmology clinics, vol 12, No 2, Boston, 1972, Little, Brown & Company, p 169. Krill AE, and Klien BA: Flecked retina syndrome, Arch Ophthalmol 74:496, 1965. Caine R, Albert DM, Lahav M, and Bullock J: Oxalate retinopathy: An experimental model of a flecked retina, Invest Ophthalmol 14:359, 1975.
939
"'Flecked retina"--an association with primary hyperoxaluria A chiM with hyperoxaluria, probable Type L was noted to have a "flecked retina" on funduscopic examination at age 289 months," it persisted throughout his seven years of life. The relationship of the ocular findings to his metabolic disease is discussed.
Ruth P. Gottlieb, M.D.,* and Joseph A. Ritter, M.D., Philadelphia, Pa.
PRIMARY HYPEROXALURIA is an autosomal recessive inherited disorder of glyoxylate metabolism characterized by calcium oxalate deposition in m a n y organs of the body? -~ To our knowledge, no record of involvement of the eyes in patients with oxalosis is available, other than that of retinal deposition of calcium oxalate in an adult with oxalosis secondary to anesthesia with methoxyflurane.s. ~, We have observed a child with primary hyperoxaluria, probable Type I, who had retinal changes which appear similar to, but more extensive than, those described by Bullock and Albert ~ and Albert and associates?' In the latter case, deposition of calcium oxalate in the retina was confirmed. This retinal appearance, termed "flecked retina," was noted in our patient at age 2J/2 months and persisted throughout his seven years of life. Recognition of this retinal appearance may aid in early diagnosis of primary hyperoxaluria.
CASE REPORT Patient S. T., a 2,400 gm boy, was born of a 15-year-old, gravida 1, para 1, black woman after an uneventful 40-week gestation. The neonatal period was normal, but during the first two months of life he evidenced increasing lethargy which led to hospitalization at Philadelphia General Hospital at age 289 months. On admission he was febrile, dehydrated, severely anemic (hemoglobin 6.5 gm/dl), acidotic (pH 7.12), and uremic (BUN 65 mg/dl). Initial physical examination revealed poor From the Department of Pediatrics, Jefferson Medical College of Thomas Jefferson University, and the University of Pennsylvania School of Medicine. *Reprint address: Jefferson Medical College, 1025 Walnut St., Philadelphia, PA 1910Z
tissue turgor, but was otherwise unremarkable except for the ocular findings. The ocular muscle balance was normal; funduscopy revealed innumerable, discrete, white pinhead-size lesions diffusely scattered throughout the posterior pole of both eyes (Fig. 1). These lesions were within or behind the sensory retina, spared the macula, and were more dense toward the equator. There was neither vitreous haze nor retinal pigmentary changes. At 9 months of age, he was noted to have pendular ocular nystagmus, and re-examination of the fundus revealed the white punctate lesions to be unchanged, but both maculae showed fairly well-circumscribed, semitransparent, yellowish white, dome-shaped elevations. Several months later, a fluorescein fundus study revealed that the punctate retinal lesions acquired fluorescence during the choroidal phase and did not change in size or intensity with time. There was marked pooling and leaking of fluorescein in tha macular areas, which persisted throughout the 30-minute examination. When he was 4 years old, repeat funduscopic examination again revealed the multiple punctate retinal lesions, but now considerable macular scarring was present (Fig. 2). Visual acuity could not be accurately determined at this time, but the child could identify objects the size of a pen. [
Abbreviations used CMV: cytomegalovirus RPE: retinal pigment epithelium
[
At age 8 months, an open renal biopsy was performed in order to clarify the child's persistent anemia, acidosis, and uremia. The biopsied tissue contained massive intraluminal deposition of birefringent crystals arranged as radiating sheaves to form rosettes characteristic of calcium oxalate. When he was 81/2 months of age, the 24-hour urinary excretion of oxalate was 24 mg or 120 mg/1.73 M ~ (normal value ~ 55 rag/24 hour/l.73 M~). Subsequent determinations showed oxalate excretions of 98 to 288 rag/24 hr/1.73 M ~. The urine was also analyzed for
Vol. 90, No. 6, pp. 939-942
940
Gottlieb and Ritter
The Journal of Pediatrics June 1977
Fig. 1. Ocular fundus at age 25 months.
Fig. 2. Ocular fundus at age 4 years. glycolate and glycerate: the former was 40 mg/24 hour or 119 mg/24 hour/1.73 M'-', and the latter was undetectable (normal value for glycolate excretion ___60 mg/24 hour/1.73 M-'; no glycerate should be detectable). During this hospitalization, studies of urine, blood, and renal tissue for cytomegalovirus isolation were performed: all were indicative of CMV infection. At age 4 years, the child was admitted to Thomas Jefferson University Hospital because of increasing bone pain and radiographic demonstration of cystic lesions throughout the pelvis and both upper and lower extremities. A bone biopsy taken from the iliac crest showed birefringent crystalline deposits in the marrow consistent with calcium oxalate deposition.
The child was treated symptomatically with pyridoxine, magnesium oxide, alkalinizing solutions, and vitamin D; however, renal function progressively deteriorated and at age 7 years he died in uremia. A limited autopsy was performed. demonstrating progression of the renal and bone pathology. Examination of the eyes and brain was not permitted. DISCUSSION Primary hyperoxaluria is a n inherited metabolic disorder o f glyoxylate m e t a b o l i s m d u e to a deficiency o f the cytoplasmic enzyme 2-oxo-glutarate: glyoxylate carboligase (Type I) that is responsible for increased
Volume 90 Number 6
urinary excretion of oxalate and glycolate,'" or to a deficiency of D-glyceric dehydrogenase (Type II) leading to increased urinary excretion of oxalate and glycerate. '~ Although the most common presenting symptoms relate to the presence of nephrolithiasis, extrarenal deposition has been reported in bones -~ heart,: ..... male genital tract,' central nervous system, '~, ~ and in the media of large, medium, and small arteries.:' Infants with this disorder may present with symptoms of renal failure, have nephrocalcinosis without nephrolithiasis, and die in renal failure before reaching one year of age. ~ Our patient presumably had hyperoxaluria Type I as indicated by the elevated urinary excretion of oxalate and glycolate. The renal biopsy showing massive intraluminal deposition of birefringent crystals and the bone biopsy showing birefringent crystalline deposits in the marrow are characteristic pathologic findings of primary hyperoxaluria.'. '~ Death from chronic renal failure is clinically characteristic of this disorder. '~ The child's illness was initially thought to be due to CMV infection and indeed may have been complicated by it. However, the punctate retinal lesions evident at age 2V,. months, followed by retinal pigment epithelium detachment in the macular area, with subsequent macular scarring, and a fluorescein fundus study suggestive of a lesion at the level of the retinal pigment epithelium, to our knowledge, have not been described previously in cytomegalovirus inclusion disease or in primary hyperoxaluria. The usual ocular picture of acute CMV infection includes broad, widely distributed patches of yellow-white granular material representing acute retinal necrosis, extensive flame-shaped intraretinal hemorrhage, and arteriolar attenuation or sheathing as a result of necrosis of vessel walls. ':~The ocular signs of healed chorioretinitis following CMV infection are nonspecific: they include pleomorphic chorioretinal scars, which have white centers of exposed sclera bordered by dense, black rims of accumulated pigment. H. '.; Although no similar reports of calcium oxalate deposition in the retina have been located in patients with primary hyperoxaluria, Bullock and AlberP have reported the fundus changes in oxalosis secondary to methoxyflurane anesthesia. The ocular fundi in their patient were normal prior to surgery in which methoxyflurane was used for anesthesia; funduscopic examination three years later revealed numerous yellowish white punctate lesions diffusely scattered throughout the posterior poles and midperiphery of both eyes. The appearance of the optic discs, maculae, and vessels was normal. A second patient reported by Albert and colleagues" also developed similar fundus lesions following methoxyflurane anesthesia, Fluorescein angiography showed faint "window defects"
Flecked retina
94 1
corresponding to the appearance of the lesions. No late staining was seen in the area of the lesions. In the first patient, pathologic study of the eyes postmortem showed the vitreous, choroid, disc, and sclera to be normal; the retinal pigment epithelium contained extensive crystalline deposits exhibiting birefringence when examined under polarized filters. The choroid and choriocapillaris were unremarkable as were the optic nerve and sclera. Radiation diffraction and optical index studies on identical crystals removed from the kidney positively identified the crystals as calcium oxalate. Pathologic examination of the eyes of the second patient was not permitted. The authors ~ called the fundus appearance "flecked retina," a term originally applied by Krill and Klien ' ' to several conditions with a similar appearance of the fundus (fundus albipunctatus, fundus flavimaculatus, and colloid bodies or drusen). Caine and associates 'T produced a "flecked retina" in rabbits by the subcutaneous injection of dibutyl oxalate. The earliest funduscopic changes were small, pinpoint, depigmented areas of the retina apparently related to a disturbance of the pigmented epithelium. On the fourth day, discrete white flecks were observed throughout the posterior pole, and in less concentration up to the equator. On histopathologic examination, the rabbits with "flecked retinas" demonstrated intracellular needle-like crystals within numerous cells of the RPE. The crystals were identified as calcium oxalate. The ocular fundus of our patient indicates a lesion at the level of the RPE, and calcium oxalate deposits were also identified in the kidney and in bone. In view of the studies reported above, it seems likely that the retinal lesions were also due to deposits of calcium oxalate in the RPE. We would like to thank Dr. Hibbard Williams for performing the urinary oxalate, glycolate, and glycerate determinations; Dr. Grant Morrow for performing the urinary oxalate determinations: Dr. Stanley Plotkin for performing CMV studies; and Dr. David Sauer and other members of the ophthalmology departments of the University of Pennsylvania School of Medicine and Jefferson Medical College of Thomas Jefferson University for performing fundus studies and photography, and for assistance in interpretation of the fundus findings. REFERENCES
I. Williams HE, and Smith LH Jr: Disorders of oxalate metabolism, Am J Med 45:715, 1968. 2. Dunn HG: Oxalosis, Am J Dis Child 90:58, 1955. 3. Davis JS, Klingberg WG, and Stowell RE: Nephrolithiasis and nephrocalcinosis with calcium oxalate crystals in kidneys and bones, J PEDIATR36:323, 1950. 4. Aponte GE, and Fetter TR: Familial idiopathic oxalate nephrocalcinosis, Am J Clin Pathol 24:1363, 1954.
942
Gottlieb and Ritter
5, Burke EC, Baggenstoss AH, Owen CA Jr, Power MH, and Lohr OW: Oxalosis, Pediatrics 15:383, 1955. 6. Chou LY, and Donohue WL: Oxalosis-a possible inborn error of metabolism, Pediatrics 10:662, 1952. 7. Katzuni E, and Sandbank U: Oxalosis, Arch Dis Child 34:60, 1959. 8. Bullock JD, and Albert DM: Flecked retina, Arch Ophthalmol 93:26, 1975. 9. Albert DM, Bullock JD, Lahav M, and Caine R: Flecked retina secondary to oxalate crystals from methoxyflurane anesthesia: Clinical and experimental studies, Trans Am Acad Ophthalmol Otolaryngol 76:817, 1975. 10. Koch J, Stokstad ELR, Williams HE, and Smith LH Jr: Deficiency of 2-oxo-glutarate: glyoxylate carboligase activity in primary hyperoxaluria, Proc Natl Acad Sci 57:1123, 1967. 11. Williams HE, and Smith LH Jr: L-Glyceric aciduria: A new
The Journal of Pediatrics June 1977
12. 13.
14.
15. 16. 17.
genetic variant of primary oxaluria, N Engl J Med 278:233, 1968. Hockaday TDR, Clayton JE, Frederick EW, and Smith LH Jr: Primary hyperoxaluria, Medicine 43:315, 1964. Wyhinny GJ, Apple DJ, Guastella FR, and Vygantas CM: Adult cytomegalic inclusion retinitis, Am J Ophthalmol 76:773, 1973. Hoyt WF, and Beeston D: In The ocular fundus in neurologic disease, St. Louis, 1966, The CV Mosby Company, p 98. Boniuk I: In International ophthalmology clinics, vol 12, No 2, Boston, 1972, Little, Brown & Company, p 169. Krill AE, and Klien BA: Flecked retina syndrome, Arch Ophthalmol 74:496, 1965. Caine R, Albert DM, Lahav M, and Bullock J: Oxalate retinopathy: An experimental model of a flecked retina, Invest Ophthalmol 14:359, 1975.
