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X-Linked Recessive Familial Exudative Vitreoretinopathy
X-Linked Recessive Familial Exudative Vitreoretinopathy D a v i d A. Plager, M.D., Ira K. Orgel, M.D., Forrest D . E l l i s , M.D., Michael Hartzer, P h . D . , M i c h a e l T. Trese, M.D., and Barkur S. Shastry, P h . D .
Familial exudative vitreoretinopathy is an inherited disorder characterized by retinal traction, peripheral vitreous opacities, and subretinal and intraretinal exudates. We ob served a family in which four boys (the chil dren of three sisters) were affected with this disorder and an X-linked recessive inheri tance was apparent. The differential diagnosis includes retinopathy of prematurity, primary hyperplastic primary vitreous, Coats' disease, peripheral uveitis, retinoblastoma, and Norrie's disease, but this differentiation can usu ally be made on the basis of clinical findings alone. Knowledge of X-linked recessive trans mission is important for correct diagnosis and for genetic counseling.
A N INHERITED vitreoretinopathy characterized by retinal traction, peripheral vitreous opaci ties, subretinal and intraretinal exudates, and retinal detachment was first described by Criswick and Schepens in 1969.' Clinically, the condition appeared to be similar to retinopathy of prematurity, b u t also h a d some findings in common with Coats' disease, peripheral uvei tis, and other retinal disorders. It developed in full-term infants and initially was described in several members of two families. Because a specific mode of inheritance could not be deter-
Accepted for publication May 8, 1992. From the Department of Ophthalmology, Section of Pediatrie Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana (Drs. Plager and Ellis); Eye Research Institute, Oakland University, Rochester, Michigan (Drs. Hartzer, Trese, and Shastry); and Beau mont Eye Institute, William Beaumont Hospital, Royal Oak, Michigan (Drs. Trese and Orgel). This study was supported in part by the National Society to Prevent Blindness, New York, New York; and in part by the Retinopathy of Prematurity Association for Research and Development (Drs. Hartzer and Shastry). Reprint requests to David A. Plager, M.D., Depart ment of Ophthalmology, Indiana University Medical Center, 702 Rotary Circle, Indianapolis, IN 46202.
mined, the new entity was called familial exu dative vitreoretinopathy. In 1971 Gow and Oliver 2 described an exten sive pedigree with these clinical findings inher ited in an autosomal dominant pattern. Several subsequent studies, including those of van Nouhuys, 3 Ober and associates, 4 Tasman and associates, 6 Nicholson and Galvis, 6 and Feldman, Norris, and Cleasby 7 also cited families with this condition that demonstrated an auto somal dominant mode of transmission. The disease also has been referred to as dominant exudative vitreoretinopathyΛ' We found evidence of an X-linked mode of inheritance for this disorder. Knowledge that this mode of transmission exists is important for both genetic counseling and diagnosis, es pecially when there is no evidence of disease or history of disease in other family members.
Case Reports Case 1 (IV-5) A 3-year-old boy was examined for progres sive intermittent deviation of the left eye. The child had been a full-term infant with a birth weight of 3,000 g, and was otherwise healthy. An older brother had undergone a surgical procedure for intermittent exotropia. The par ents noted that a younger brother (Case 2) did "not see well." Additionally, the child's moth er had one second cousin who was said to have congenital retinal folds. Another second cousin was reported to have bilateral persistent hyper plastic primary vitreous and a first cousin had been blind since birth. Examination showed central fixation of the right eye with accurate following movements, but poor following movements and wandering fixation of the left eye. There was an apparent large-angle left exotropia on testing with a light reflex, but no shift was noted on alternate cover testing (positive angle kappa). The corneal di-
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ameter was normal in each eye, there was no afferent pupillary defect, and the anterior seg ments were normal. Ophthalmoscopy of the right eye showed an avascular demarcation line near the equator for 360 degrees. A line of exudate was present just anterior to the inferior-temporal vascular ar cade demarcation line. Early traction into the vitreous of the retinal vessels in that area was apparent. The fundus of the left eye demon strated similar but more extensive abnormali ties with a white temporal mass of exudate that pulled the retinal vessels toward the temporal ora serrata and attached near the temporalposterior edge of the lens. Cycloplegic refrac tion was R.E.: - 2 . 0 0 + 0.50 X 90 and L.E.: - 1 . 5 0 + 0.50 X 90. The boy had an increase in the exudate and retinal traction of the right eye over the next several weeks and therefore underwent cryopexy and placement of a 360-degree scierai buckle in each eye. Two years postoperatively, the progression of the disease appeared to have stopped and the child had a visual acuity of R.E.: 20/40 and L.E.: 20/400. Case 2 (IV-6) A 3-month-old brother of Patient IV-5 was examined for poor visual development. He had been a full-term infant with a birth weight of 3,500 g, and was otherwise healthy. Examination showed a pendular nystagmus. The corneas were clear, although the anterior chambers were shallow. A white retrolental mass attached to the temporal side of the lens in each eye was visible. Ophthalmoscopy showed both retinas to be in a fixed fold, stretching from the optic disk to the white exudative mass temporally. Over the next two months, the left eye devel oped a dense white retrolental mass that ob scured the vitreous. A vitrectomy with mem brane peeling in each eye was performed. When last examined 16 months postopera tively, the right eye had an open funnel detach ment with a small area of retina attached at the posterior pole. The left eye had a dense retro lental membrane with no attached retina. Because of the genetic nature of this disorder, the records of the two second cousins with congenital retinal folds and bilateral persistent hyperplastic primary vitreous were obtained. Case 3 (IV-10) A 5-month-old boy, a second cousin of Pa tients IV-5 and IV-6, had been examined by a retinal specialist in North Dakota. The child
had been born at 41 weeks of gestation and was healthy. Birth weight was unknown. He was noted to have no fixation in either eye. Anterior segments were normal, with corneal diameters of 11.5 mm. Ophthalmoscopy showed large retinal folds that extended from the disks tem porally with the central retinal artery pulled from the disk so that its first bifurcation was 2 mm temporal to the disk. The temporal ret ina was drawn into a white exudative mass that was attached to the posterior temporal lens edge. Bilateral congenital retinal folds were diagnosed. Case 4 (IV-12) A 5-month-old boy, a second cousin to Pa tients IV-5 and IV-6, and first cousin to Patient IV-10, was examined by a pediatrie ophthal mologist in Florida. He had been a full-term infant and was healthy. Birth weight was un known. No fixation was present. Examination disclosed normal anterior segments. Ophthal moscopy showed an intravitreal fibrous mass and membrane that was more extensive on the right, and that extended from the disk up to the temporal posterior lens edge. Bilateral persis tent hyperplastic primary vitreous was diag nosed.
Discussion Since the original description of familial exu dative vitreoretinopathy by Criswick and Schep e n s / m a n y authors have contributed infor mation relative to the pathophysiologic characteristics of this entity. Gow and Oliver 2 described a larger family that provided evi dence of an autosomal dominant mode of inher itance. Canny and Oliver 8 described fluorescein angiographie findings that demonstrated an abrupt cessation of the retinal capillary net work with leakage of dye from the border of the existing capillaries. Additionally, large leaking retinal vessels were present in temporal retinal masses. The pathologic characteristics of familial exu dative vitreoretinopathy were described by Brockhurst, Albert, and Zakov9 in two siblings, and later by Boldrey and associates 10 in two unrelated patients. Pathologic findings includ ed vitreous membranes, vitreous detachment, prominent vitreoretinal attachments, and vitre ous condensations. Retinal pathologic findings included abrupt cessation of the capillary net work, chronic detachment, gliosis, exudate,
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X-Linked Familial Exudative Vitreoretinopathy
147
None of the 12 females in the pedigree were known to be affected. All affected males are related through female relatives. A fifth male, now deceased, was known to be blind since birth and may have been affected. We ques tioned whether this is the only family with this mode of inheritance. Review of the literature indicates otherwise. Familial exudative vitreoretinopathy in one of the two families described in Criswick and Schepens' first description 1 was probably Xlinked. In that pedigree, five of eight males were affected, none of six females was affected, and all affected males were related through their mothers and other female relatives. Dudgeon 13 described two brothers with famil ial exudative vitreoretinopathy and two of their male second cousins who also had retinal folds and temporal fibrous masses. All had been full-term infants with normal birth weights. Not one of the nine females in the families was affected, and two of their brothers were unaf fected. All affected males were related through female relatives, which suggested an X-linked recessive mode of inheritance in this family as well. Miyakubo, Inohara, and Hashimoto 14 de scribed familial exudative vitreoretinopathy in 15 families. Eleven families showed autosomal dominant transmission and four unrelated cases were termed sporadic. Notably, all four sporadic cases were in males, which raised the possibility that they were X-linked recessive. We have seen three other unrelated children with familial exudative vitreoretinopathy dur ing the past two years. None of the children had
and thickening and involution of vessels. Falci form retinal folds have also been described as a feature of this disorder. 21112 It seemed clear from the history and retinal findings described elsewhere that Patients IV10 and IV-12 had the same condition as Pa tients IV-5 and IV-6. Although Patient IV-10 did have retinal folds, it may be that congeni tal retinal folds should be considered a clini cal sign suggestive of an underlying vascularvitreal pathologic process rather than a distinct diagnostic entity. The diagnosis of bilateral persistent hyperplastic primary vitreous in patient IV-12 was suspect because persistent hyperplastic pri mary vitreous is not usually bilateral and this patient had normal córneal diameters, a finding which is not consistent with persistent hyper plastic primary vitreous. Additionally, the reti nal abnormality was connected to the temporal edge of the lens, which is not typical of persis tent hyperplastic primary vitreous. It is more likely that this patient had the same underlying condition as Patients IV-5, IV-6, and IV-10. We constructed a pedigree for this family (Figure). Patients III-l and II-1 were examined by us by using indirect ophthalmoscopy and scierai depression as well as fluorescein angiography and no retinal abnormalities were found. Specifically, there were no areas of avascular temporal retina. Additional relatives were ex amined for retinal abnormalities by other oph thalmologists and were found to be normal. In our pedigree, the entity was probably transmitted as an X-linked recessive disorder. Four of seven males examined were affected.
Ch-O
Î m IV
an 3
4
5
)-Examined, not affected
Figure (Plager and associates). Pedi gree of a family with X-linked recessive familial exudative vitreoretinopa thy.
|g
9
IO
6
1-Not examined (deceased), probably affected
|-Not examined, no symptoms
11
12
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AMERICAN JOURNAL OF OPHTHALMOLOGY
a family history of the disorder. All three are male. This entity is probably more common than is currently appreciated. It may be particularly difficult to diagnose in isolated cases, as evi denced by Cases 3 and 4. The differential diag nosis includes retinopathy of prematurity, Coats' disease, persistent hyperplastic primary vitreous, peripheral uveitis, retinoblastoma, Norrie's disease, and other retinal vascular ab normalities. However, this differential should not be difficult in typical cases on the basis of clinical findings alone. Retinopathy of prematurity develops in lowbirth-weight premature babies, who may have been exposed to oxygen. It involves shunt for mation, neovascular proliferation, and subse quent retinal traction. Exudation from leaking vessels is not a prominent finding. Coats' disease is usually unilateral and has characteristic telangiectatic vessels with mas sive yellow exudate. Retinal traction is not usually a prominent finding. Persistent hyperplastic primary vitreous is also nearly always unilateral and develops in microphthalmic eyes. A residual hyaloid artery remnant is present, which attaches to the back of the lens with a variably prominent retrolental membrane. Norrie's disease, an uncommon X-linked dis ease, may be the most difficult to differentiate. It is characterized by bilateral retinal folds or retinal masses, or both, that have been present since birth. Microphthalmia, cataract, and corneal opacification can also be present. Patients are frequently mentally retarded and hearing deficient.1516 Confusion of familial exudative vitreoretinopathy with other retinal lesions should not be common. However, knowledge that familial exudative vitreoretinopathy exists as an X-link ed disorder should help alert ophthalmologists to the possibility of this disease, especially in children who have retinal folds, or the earlier stages of retinal traction, exudate, or avascular peripheral retina. Correct diagnosis is impor tant so that appropriate patient examination, examination of family members, and genetic counseling can be performed. Treatment of the peripheral vascular abnormalities at an early stage may be helpful in slowing or preventing progression of this potentially blinding disor der. Laboratory study using genetic linkage anal ysis is currently underway in an effort to identi
fy the gene responsible for this disorder. This will be of great value in identifying asympto matic female carriers, which has not been pos sible on clinical signs alone.
References 1. Criswick, V. G., and Schepens, C. L.: Familial exudative vitreoretinopathy. Am. J. Ophthalmol. 68:578, 1969. 2. Gow, J., and Oliver, G. L.: Familial exudative vitreoretinopathy. An expanded view. Arch. Oph thalmol. 86:150, 1971. 3. van Nouhuys, C. E.: Dominant exudative vitre oretinopathy. Ophthalmic Pediatr. Genet. 5:31, 1985. 4. Ober, R. R„ Bird, A. C , Hamilton, A. M., and Sehmi, K.: Autosomal dominant exudative vitreoreti nopathy. Br. J. Ophthalmol. 64:112, 1980. 5. Tasman, W., Augsburger, J. J., Shields, J. A„ Caputo, A., and Annesley, W. H., Jr.: Familial exuda tive vitreoretinopathy. Trans. Am. Ophthalmol. Soc. 79:211, 1981. 6. Nicholson, D. H., and Galvis, V.: CriswickSchepens syndrome (familial exudative vitreoreti nopathy). Arch. Ophthalmol. 102:1519, 1984. 7. Feldman, E. L., Norris, J. L., and Cleasby, G. W.: Autosomal dominant exudative vitreoretinop athy. Arch. Ophthalmol. 101:1532, 1983. 8. Canny, C. L., and Oliver, G. L.: Fliiorescein an giographie findings in familial exudative vitreoreti nopathy. Arch. Ophthalmol. 94:1114, 1976. 9. Brockhurst, R., Albert, P. M., and Zakov, Z. N.: Pathologic findings in familial exudative vitreoreti nopathy. Arch. Ophthalmol. 99:2143, 1981. 10. Boldrey, E., Egbert, P., Gass, D. M., and Freberg, T.: The histopathology of familial exudative vitreoretinopathy. A report of two cases. Arch. Oph thalmol. 103:238, 1985. 11. van Nouhuys, C. E.: Congenital retinal fold as a sign of dominant exudative vitreoretinopathy. Graefes Arch. Clin. Exp. Ophthalmol. 217:55, 1981. 12. Nishimura, M., Yamana, T., Sugino, M., Kohno, T., Yamana, Y., Minei, M., and Sanui, H.: Falciform retinal fold as sign of familial exudative vitreoretinopathy. Jpn. J. Ophthalmol. 27:40, 1983. 13. Dudgeon, J.: Familial exudative vitreoretinop athy. Trans. Ophthalmol. Soc. U.K. 99:45, 1979. 14. Miyakubo, H., Inohara, N., and Hashimoto, K.: Retinal involvement in familial exudative vitreoreti nopathy. Ophthalmologica 185:125, 1982. 15. Hausen, A. C : Norrie's disease. Am. J. Oph thalmol. 66:328, 1968. 16. Jacklin, H. N.: Falciform fold, retinal detach ment, and Norrie's disease. Am. J. Ophthalmol. 90:76, 1980.
Familial exudative vitreoretinopathy is an inherited disorder characterized by retinal traction, peripheral vitreous opacities, and subretinal and intraretinal exudates. We ob served a family in which four boys (the chil dren of three sisters) were affected with this disorder and an X-linked recessive inheri tance was apparent. The differential diagnosis includes retinopathy of prematurity, primary hyperplastic primary vitreous, Coats' disease, peripheral uveitis, retinoblastoma, and Norrie's disease, but this differentiation can usu ally be made on the basis of clinical findings alone. Knowledge of X-linked recessive trans mission is important for correct diagnosis and for genetic counseling.
A N INHERITED vitreoretinopathy characterized by retinal traction, peripheral vitreous opaci ties, subretinal and intraretinal exudates, and retinal detachment was first described by Criswick and Schepens in 1969.' Clinically, the condition appeared to be similar to retinopathy of prematurity, b u t also h a d some findings in common with Coats' disease, peripheral uvei tis, and other retinal disorders. It developed in full-term infants and initially was described in several members of two families. Because a specific mode of inheritance could not be deter-
Accepted for publication May 8, 1992. From the Department of Ophthalmology, Section of Pediatrie Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana (Drs. Plager and Ellis); Eye Research Institute, Oakland University, Rochester, Michigan (Drs. Hartzer, Trese, and Shastry); and Beau mont Eye Institute, William Beaumont Hospital, Royal Oak, Michigan (Drs. Trese and Orgel). This study was supported in part by the National Society to Prevent Blindness, New York, New York; and in part by the Retinopathy of Prematurity Association for Research and Development (Drs. Hartzer and Shastry). Reprint requests to David A. Plager, M.D., Depart ment of Ophthalmology, Indiana University Medical Center, 702 Rotary Circle, Indianapolis, IN 46202.
mined, the new entity was called familial exu dative vitreoretinopathy. In 1971 Gow and Oliver 2 described an exten sive pedigree with these clinical findings inher ited in an autosomal dominant pattern. Several subsequent studies, including those of van Nouhuys, 3 Ober and associates, 4 Tasman and associates, 6 Nicholson and Galvis, 6 and Feldman, Norris, and Cleasby 7 also cited families with this condition that demonstrated an auto somal dominant mode of transmission. The disease also has been referred to as dominant exudative vitreoretinopathyΛ' We found evidence of an X-linked mode of inheritance for this disorder. Knowledge that this mode of transmission exists is important for both genetic counseling and diagnosis, es pecially when there is no evidence of disease or history of disease in other family members.
Case Reports Case 1 (IV-5) A 3-year-old boy was examined for progres sive intermittent deviation of the left eye. The child had been a full-term infant with a birth weight of 3,000 g, and was otherwise healthy. An older brother had undergone a surgical procedure for intermittent exotropia. The par ents noted that a younger brother (Case 2) did "not see well." Additionally, the child's moth er had one second cousin who was said to have congenital retinal folds. Another second cousin was reported to have bilateral persistent hyper plastic primary vitreous and a first cousin had been blind since birth. Examination showed central fixation of the right eye with accurate following movements, but poor following movements and wandering fixation of the left eye. There was an apparent large-angle left exotropia on testing with a light reflex, but no shift was noted on alternate cover testing (positive angle kappa). The corneal di-
©AMERICAN JOURNAL OF OPHTHALMOLOGY 114:145-148, AUGUST, 1992
145
146
August, 1992
AMERICAN JOURNAL OF OPHTHALMOLOGY
ameter was normal in each eye, there was no afferent pupillary defect, and the anterior seg ments were normal. Ophthalmoscopy of the right eye showed an avascular demarcation line near the equator for 360 degrees. A line of exudate was present just anterior to the inferior-temporal vascular ar cade demarcation line. Early traction into the vitreous of the retinal vessels in that area was apparent. The fundus of the left eye demon strated similar but more extensive abnormali ties with a white temporal mass of exudate that pulled the retinal vessels toward the temporal ora serrata and attached near the temporalposterior edge of the lens. Cycloplegic refrac tion was R.E.: - 2 . 0 0 + 0.50 X 90 and L.E.: - 1 . 5 0 + 0.50 X 90. The boy had an increase in the exudate and retinal traction of the right eye over the next several weeks and therefore underwent cryopexy and placement of a 360-degree scierai buckle in each eye. Two years postoperatively, the progression of the disease appeared to have stopped and the child had a visual acuity of R.E.: 20/40 and L.E.: 20/400. Case 2 (IV-6) A 3-month-old brother of Patient IV-5 was examined for poor visual development. He had been a full-term infant with a birth weight of 3,500 g, and was otherwise healthy. Examination showed a pendular nystagmus. The corneas were clear, although the anterior chambers were shallow. A white retrolental mass attached to the temporal side of the lens in each eye was visible. Ophthalmoscopy showed both retinas to be in a fixed fold, stretching from the optic disk to the white exudative mass temporally. Over the next two months, the left eye devel oped a dense white retrolental mass that ob scured the vitreous. A vitrectomy with mem brane peeling in each eye was performed. When last examined 16 months postopera tively, the right eye had an open funnel detach ment with a small area of retina attached at the posterior pole. The left eye had a dense retro lental membrane with no attached retina. Because of the genetic nature of this disorder, the records of the two second cousins with congenital retinal folds and bilateral persistent hyperplastic primary vitreous were obtained. Case 3 (IV-10) A 5-month-old boy, a second cousin of Pa tients IV-5 and IV-6, had been examined by a retinal specialist in North Dakota. The child
had been born at 41 weeks of gestation and was healthy. Birth weight was unknown. He was noted to have no fixation in either eye. Anterior segments were normal, with corneal diameters of 11.5 mm. Ophthalmoscopy showed large retinal folds that extended from the disks tem porally with the central retinal artery pulled from the disk so that its first bifurcation was 2 mm temporal to the disk. The temporal ret ina was drawn into a white exudative mass that was attached to the posterior temporal lens edge. Bilateral congenital retinal folds were diagnosed. Case 4 (IV-12) A 5-month-old boy, a second cousin to Pa tients IV-5 and IV-6, and first cousin to Patient IV-10, was examined by a pediatrie ophthal mologist in Florida. He had been a full-term infant and was healthy. Birth weight was un known. No fixation was present. Examination disclosed normal anterior segments. Ophthal moscopy showed an intravitreal fibrous mass and membrane that was more extensive on the right, and that extended from the disk up to the temporal posterior lens edge. Bilateral persis tent hyperplastic primary vitreous was diag nosed.
Discussion Since the original description of familial exu dative vitreoretinopathy by Criswick and Schep e n s / m a n y authors have contributed infor mation relative to the pathophysiologic characteristics of this entity. Gow and Oliver 2 described a larger family that provided evi dence of an autosomal dominant mode of inher itance. Canny and Oliver 8 described fluorescein angiographie findings that demonstrated an abrupt cessation of the retinal capillary net work with leakage of dye from the border of the existing capillaries. Additionally, large leaking retinal vessels were present in temporal retinal masses. The pathologic characteristics of familial exu dative vitreoretinopathy were described by Brockhurst, Albert, and Zakov9 in two siblings, and later by Boldrey and associates 10 in two unrelated patients. Pathologic findings includ ed vitreous membranes, vitreous detachment, prominent vitreoretinal attachments, and vitre ous condensations. Retinal pathologic findings included abrupt cessation of the capillary net work, chronic detachment, gliosis, exudate,
Vol. 114, No. 2
X-Linked Familial Exudative Vitreoretinopathy
147
None of the 12 females in the pedigree were known to be affected. All affected males are related through female relatives. A fifth male, now deceased, was known to be blind since birth and may have been affected. We ques tioned whether this is the only family with this mode of inheritance. Review of the literature indicates otherwise. Familial exudative vitreoretinopathy in one of the two families described in Criswick and Schepens' first description 1 was probably Xlinked. In that pedigree, five of eight males were affected, none of six females was affected, and all affected males were related through their mothers and other female relatives. Dudgeon 13 described two brothers with famil ial exudative vitreoretinopathy and two of their male second cousins who also had retinal folds and temporal fibrous masses. All had been full-term infants with normal birth weights. Not one of the nine females in the families was affected, and two of their brothers were unaf fected. All affected males were related through female relatives, which suggested an X-linked recessive mode of inheritance in this family as well. Miyakubo, Inohara, and Hashimoto 14 de scribed familial exudative vitreoretinopathy in 15 families. Eleven families showed autosomal dominant transmission and four unrelated cases were termed sporadic. Notably, all four sporadic cases were in males, which raised the possibility that they were X-linked recessive. We have seen three other unrelated children with familial exudative vitreoretinopathy dur ing the past two years. None of the children had
and thickening and involution of vessels. Falci form retinal folds have also been described as a feature of this disorder. 21112 It seemed clear from the history and retinal findings described elsewhere that Patients IV10 and IV-12 had the same condition as Pa tients IV-5 and IV-6. Although Patient IV-10 did have retinal folds, it may be that congeni tal retinal folds should be considered a clini cal sign suggestive of an underlying vascularvitreal pathologic process rather than a distinct diagnostic entity. The diagnosis of bilateral persistent hyperplastic primary vitreous in patient IV-12 was suspect because persistent hyperplastic pri mary vitreous is not usually bilateral and this patient had normal córneal diameters, a finding which is not consistent with persistent hyper plastic primary vitreous. Additionally, the reti nal abnormality was connected to the temporal edge of the lens, which is not typical of persis tent hyperplastic primary vitreous. It is more likely that this patient had the same underlying condition as Patients IV-5, IV-6, and IV-10. We constructed a pedigree for this family (Figure). Patients III-l and II-1 were examined by us by using indirect ophthalmoscopy and scierai depression as well as fluorescein angiography and no retinal abnormalities were found. Specifically, there were no areas of avascular temporal retina. Additional relatives were ex amined for retinal abnormalities by other oph thalmologists and were found to be normal. In our pedigree, the entity was probably transmitted as an X-linked recessive disorder. Four of seven males examined were affected.
Ch-O
Î m IV
an 3
4
5
)-Examined, not affected
Figure (Plager and associates). Pedi gree of a family with X-linked recessive familial exudative vitreoretinopa thy.
|g
9
IO
6
1-Not examined (deceased), probably affected
|-Not examined, no symptoms
11
12
148
August, 1992
AMERICAN JOURNAL OF OPHTHALMOLOGY
a family history of the disorder. All three are male. This entity is probably more common than is currently appreciated. It may be particularly difficult to diagnose in isolated cases, as evi denced by Cases 3 and 4. The differential diag nosis includes retinopathy of prematurity, Coats' disease, persistent hyperplastic primary vitreous, peripheral uveitis, retinoblastoma, Norrie's disease, and other retinal vascular ab normalities. However, this differential should not be difficult in typical cases on the basis of clinical findings alone. Retinopathy of prematurity develops in lowbirth-weight premature babies, who may have been exposed to oxygen. It involves shunt for mation, neovascular proliferation, and subse quent retinal traction. Exudation from leaking vessels is not a prominent finding. Coats' disease is usually unilateral and has characteristic telangiectatic vessels with mas sive yellow exudate. Retinal traction is not usually a prominent finding. Persistent hyperplastic primary vitreous is also nearly always unilateral and develops in microphthalmic eyes. A residual hyaloid artery remnant is present, which attaches to the back of the lens with a variably prominent retrolental membrane. Norrie's disease, an uncommon X-linked dis ease, may be the most difficult to differentiate. It is characterized by bilateral retinal folds or retinal masses, or both, that have been present since birth. Microphthalmia, cataract, and corneal opacification can also be present. Patients are frequently mentally retarded and hearing deficient.1516 Confusion of familial exudative vitreoretinopathy with other retinal lesions should not be common. However, knowledge that familial exudative vitreoretinopathy exists as an X-link ed disorder should help alert ophthalmologists to the possibility of this disease, especially in children who have retinal folds, or the earlier stages of retinal traction, exudate, or avascular peripheral retina. Correct diagnosis is impor tant so that appropriate patient examination, examination of family members, and genetic counseling can be performed. Treatment of the peripheral vascular abnormalities at an early stage may be helpful in slowing or preventing progression of this potentially blinding disor der. Laboratory study using genetic linkage anal ysis is currently underway in an effort to identi
fy the gene responsible for this disorder. This will be of great value in identifying asympto matic female carriers, which has not been pos sible on clinical signs alone.
References 1. Criswick, V. G., and Schepens, C. L.: Familial exudative vitreoretinopathy. Am. J. Ophthalmol. 68:578, 1969. 2. Gow, J., and Oliver, G. L.: Familial exudative vitreoretinopathy. An expanded view. Arch. Oph thalmol. 86:150, 1971. 3. van Nouhuys, C. E.: Dominant exudative vitre oretinopathy. Ophthalmic Pediatr. Genet. 5:31, 1985. 4. Ober, R. R„ Bird, A. C , Hamilton, A. M., and Sehmi, K.: Autosomal dominant exudative vitreoreti nopathy. Br. J. Ophthalmol. 64:112, 1980. 5. Tasman, W., Augsburger, J. J., Shields, J. A„ Caputo, A., and Annesley, W. H., Jr.: Familial exuda tive vitreoretinopathy. Trans. Am. Ophthalmol. Soc. 79:211, 1981. 6. Nicholson, D. H., and Galvis, V.: CriswickSchepens syndrome (familial exudative vitreoreti nopathy). Arch. Ophthalmol. 102:1519, 1984. 7. Feldman, E. L., Norris, J. L., and Cleasby, G. W.: Autosomal dominant exudative vitreoretinop athy. Arch. Ophthalmol. 101:1532, 1983. 8. Canny, C. L., and Oliver, G. L.: Fliiorescein an giographie findings in familial exudative vitreoreti nopathy. Arch. Ophthalmol. 94:1114, 1976. 9. Brockhurst, R., Albert, P. M., and Zakov, Z. N.: Pathologic findings in familial exudative vitreoreti nopathy. Arch. Ophthalmol. 99:2143, 1981. 10. Boldrey, E., Egbert, P., Gass, D. M., and Freberg, T.: The histopathology of familial exudative vitreoretinopathy. A report of two cases. Arch. Oph thalmol. 103:238, 1985. 11. van Nouhuys, C. E.: Congenital retinal fold as a sign of dominant exudative vitreoretinopathy. Graefes Arch. Clin. Exp. Ophthalmol. 217:55, 1981. 12. Nishimura, M., Yamana, T., Sugino, M., Kohno, T., Yamana, Y., Minei, M., and Sanui, H.: Falciform retinal fold as sign of familial exudative vitreoretinopathy. Jpn. J. Ophthalmol. 27:40, 1983. 13. Dudgeon, J.: Familial exudative vitreoretinop athy. Trans. Ophthalmol. Soc. U.K. 99:45, 1979. 14. Miyakubo, H., Inohara, N., and Hashimoto, K.: Retinal involvement in familial exudative vitreoreti nopathy. Ophthalmologica 185:125, 1982. 15. Hausen, A. C : Norrie's disease. Am. J. Oph thalmol. 66:328, 1968. 16. Jacklin, H. N.: Falciform fold, retinal detach ment, and Norrie's disease. Am. J. Ophthalmol. 90:76, 1980.