Congenital blindness and osteoporosis-pseudoglioma syndrome

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Congenital Blindness and OsteoporosisPseudoglioma Syndrome Dave H. Lee, MD,a Deborah Wenkert, MD,b Michael P. Whyte, MD,b,c Michael T. Trese, MDd and Oscar A. Cruz, MDa Isteoporosis-pseudoglioma syndrome (OPPG) is a rare heritable entity that features severe osteoporosis and many variable ophthalmic findings leading to congenital or juvenile blindness. These include microphthalmos, cataracts, bilateral pseudogliomatous retinal detachments, and phthisis bulbi. OPPG is usually not suspected until fractures occur, frequently after seemingly minor trauma. We report the ophthalmic findings of an infant girl with OPPG.

CASE REPORT A 4-day-old white baby was referred to the pediatric ophthalmology clinic for evaluation of absent red reflexes bilaterally, noted on the routine newborn examination. She was born by spontaneous vaginal delivery at 38 weeks gestation to a gravida 5, para 5, 24-year-old woman. Birth weight was 5 pounds 9 ounces. The patient was the result of a consanguineous relationship (aunt and nephew). The pregnancy was complicated by lack of prenatal care, drug abuse (amphetamines), tobacco use, and genital herpes infection. Four half-siblings were reportedly in good health. Initial ophthalmologic examination showed uncentral, unsteady, unmaintained visual acuity in both eyes with bilateral retinal detachments. Subsequent evaluation under anesthesia showed similar findings in both eyes, including clear corneas (diameters of 8.5 mm horizontally by 8.0 mm vertically), shallow anterior chambers, radial iris vessels extending onto the anterior lens capsule, white vascularized membranes on the posterior lens capsule, and almost complete retinal detachments. A-scan ultrasound demonstrated axial lengths of 15.1 mm in the right eye and 14.7


St Louis University Eye Institute, St Louis, Mo. Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St Louis, Mo. c Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital, St Louis, Mo. d Associated Retinal Consultants, PC, Royal Oaks, Mich. Supported by grant No. 8580 from Shriners Hospitals for Children and by The Clark and Mildred Cox Inherited Metabolic Bone Disease Research Fund. Submitted April 17, 2002. Revisions accepted August 26, 2002. Reprint requests: Oscar A. Cruz, MD, St Louis University Eye Institute, 1755 S Grand Blvd, St Louis, MO 63104.; e-mail, [email protected] J AAPOS 2003;7:75-7. Copyright © 2003 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2003/$35.00 ⫹ 0 doi:10.1016/S1091(03)00051-X b

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mm in the left eye (the normal for a newborn is 17.02 mm).1 At 5 months of age, the patient underwent lensectomy, vitrectomy, membrane peel, and fluid-air exchange in both eyes consecutively without complication. Her postoperative course was unremarkable, and the examination 3 months postoperatively showed uncentral, roving, unmaintained visual acuity in both eyes. Intraocular pressures by Schio¨tz tonometry were 34 mm Hg in the right eye and 3 mm Hg in the left. The right eye was aphakic with a small area of retina attached superiorly. The left eye was prephthisical. At 11 months of age, she sustained bilateral distal femur fractures after her adoptive parent fell while holding her. These were treated with spica casts. During evaluation of the fractures, she was found to have generalized osteopenia. A skeletal radiographic survey at age 12 months showed coarse trabecular structures and thin cortices (Figures 1 and 2). Routine biochemical parameters of mineral and skeletal homeostasis were unremarkable, except for a slightly elevated serum total calcium level (ionized calcium level was normal). The results of the urine amino acid profile were normal. There was microcephaly, generalized bypotonia, and hyperextensibility of all joints, most prominently in the shoulders and hips. Mental and social development and intelligence have been normal.

DISCUSSION OPPG is a rare heritable condition (MIM# 259770) that has been described mainly in genetic and orthopedic publications.2-5 However, despite its important ophthalmic manifestations, there are few reports concerning it in the ophthalmology literature. In most reported cases of OPPG, the ocular manifestations are noted in the neonatal period.2-6 Congenital vitreoretinal dysplasia is the most important ocular finding. It is nonspecific and occurs in a variety of settings, including bilateral persistent fetal vasculature, Norrie’s disease, trisomy 13 syndrome, and congenital infection with toxoplasmosis, cytomegalovirus, or syphilis.7 The combined ocular and skeletal pathology characterizes and distinguishes OPPG. The principal ocular morbidity is congenital or juvenile onset of blindness. In the congenital cases, the pathogenesis seems to be severe vitreoretinal dysplasia. Later onset of blindness often results from a secondary insult, such as February 2003



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FIG 1. Lateral radiograph of skull at age 12 months shows generalized osteopenia (decreased bone density) and some wormian bones (arrows) at lamboidal suture.

FIG 2. Anteroposterior radiograph of femora and knees shows coxa valga, diffuse osteopenia, bowing deformity of femora, with old fracture deformity at distal left femur (arrow).

acute glaucoma in an eye with less severe vitreoretinal disorganization.2 Histological examination of the retrolenticular mass often found in these patients has shown pseudoglioma rather than true tumor, thus establishing the moniker.5 Eyes in OPPG are microphthalmic and can exhibit microcornea, corneal opacification, and cataracts.2

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Skeletal manifestations of OPPG include generalized osteopenia with coarse trabecular structures and thin cortices (Figures 1 and 2). Typically, there is short stature, hypotonia, and hyperextensibility of joints. Intelligence in patients with OPPG varies from near normal to mildly retarded.2-6 OPPG is transmitted as an autosomal recessive trait. The osteoporosis pseudoglioma (OPS) locus has been mapped to chromosome 11q12-13.8 Recently, a mutation in the gene that encodes the low-density lipoprotein receptor-related protein 5 (LRP5) was discovered to be a cause of OPPG.9 The exact pathogenesis of OPPG remains unknown. Previous investigators have speculated a defect in the collagen matrix. However, morphologic and biochemical studies from skin samples of patients with OPPG have shown normal collagen.4 The defect might lie in collagen homeostasis rather than in primary structure. Studies of LRP5 indicate that this gene affects bone accrual during growth by regulating osteoblastic proliferation.9 Furthermore, it is hypothesized that transient expression of LRP5 by normal vitreous cells might initiate regression of the primary vitreous, and a defect in this protein results in vitreoretinal dysplasia.9 Children with OPPG suffer considerable ocular and skeletal morbidity. OPPG should be included in the differential diagnosis of children with bilateral retinal detachments and microphthalmia, especially when there is consanguinity. Early vitreoretinal surgery has been performed with some visual success in other cases of vitreoretinal dysplasia.7 However, in OPPG, the main benefit might be to preserve the globe by delaying phthisis bulbi. Suspicion of this entity could reduce fracture incidence by aggressive screening for osteopenia and careful handling of the child. Experimentally, intravenous bisphosphonates have been shown to be of some benefit in spinal osteoporosis.10 Physical therapy and awareness of the fragility of their bones, with recommendations similar to those given to children with other forms of significant osteoporosis (eg, not lifting heavy items), can minimize orthopedic morbidity in these patients. Additionally, correct diagnosis would enable appropriate genetic counseling for future generations. References 1. Grignolo A, Rivara A. Biometry of the human eye from the sixth month of pregnancy to the tenth year of life. In: Vanysek J, editor. Diagnostica ultrasonica in ophthalmologia. Brno, Czechoslovakia: Universita J. E. Purkynje; 1968. p. 251. 2. Frontali M, Stomeo C, Dallapiccola B. Osteoporosis-pseudoglioma syndrome: report of three affected sibs and an overview. Am J Med Genet 1985;22:35-47. 3. McDowell CL, Moore JD. Multiple fractures in a child: the osteoporosis pseudoglioma syndrome. A case report. J Bone Joint Surg 1992;74:1247-9. 4. De Paepe A, Leroy JG, Nuytinck L, Meire F, Capoen J. Osteoporosis-pseudoglioma syndrome. Am J Med Genet 1993;45:30-7.

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5. Bartsocas CS, Zeis PM, Elia M, Papadatos CJ. Syndrome of osteoporosis with pseudoglioma. Ann Gen 1982;25:61-2. 6. Wilson G, Moore A, Allgrove J. Bilateral retinal detachments at birth: the osteoporosis pseudoglioma syndrome. Br J Ophthalmol 2001;85:1139. 7. de Juan E, Jr, Farr AK, Noorily S. Retinal detachment in infants. In: Ryan SJ, editor. Retina. St Louis: Mosby; 2001. p. 2498-520. 8. Gong Y, Vikkula M, Boon L, Liu J, Beighton P, Rumesar R , et al. Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal


strength and vision, is assigned to chromosome region 11q12-13. Am J Hum Genet 1996;56:146-51. 9. Gong Y, Slee RB, Fukai N, Rawadi G, Heegers S, Sabatakos G, et al. LDL receptor related protein 5 (LRP5) affects bone accrual and eye development. Cell 2001;107:513-23. 10. Zacharin M, Cundy T. Osteoporosis pseudoglioma syndrome: treatment of spinal osteoporosis with intravenous bisphosphonates. J Pediatr 2000;137:410-15.

An Eye on the Arts – The Arts on the Eye

In that photo, which I still have, my father is standing in front of his plane, a hotshot, a pilot extraordinaire, already with two kills to his credit. He was just twenty-one years old. He’s bare-chested and muscular, arms crossed, teeth bared in a dazzling smile. The hazy blueness of his eyes is noticeable even on black-and-white film. There was no doubt in Grandpa’s mind about whose son I was. I had the same eyes as my father, and Grandpa recognized them immediately. “All babies have blue eyes when they’re born,” he said later, as he was telling me the story of my arrival, “but most grow out of ’em. Mann eyes are always blue, come hell or high water. And they’re not the same blue as other families. Take the Simpsons up the hill. They’ve got eyes like muddy water. Blue, but muddy, like there was some brown mixed in there. You can tell everything about a man by his eyes. There’s not a member of our family that’s lost a staring contest yet. As for those Simpsons—stay the hell away from them. Folks with eyes like that have got plenty to hide.” —William Kowalski (from Eddie’s Bastard)

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