Biomedical subjects
Publications and source records attributed to D S Walton.
Norrie disease is a rare, X-linked recessive disorder characterized by congenital blindness due to malformed retinas. We describe a simplex patient who had leukokoria and whose clinical diagnosis was confirmed only after molecular genetics analysis. DNA analysis was also used to determine the carrier status of relatives of the proband.
OBJECTIVE: To evaluate the risk of intraocular pressure (IOP) elevation in patients receiving inhaled steroid therapy. DESIGN: Prospective study. SETTING: Four private practices in New Jersey. PATIENTS: A total of 187 patients (99 men and 88 women) with no documented history of glaucoma about to begin inhaled steroid therapy for various pulmonary conditions were enrolled. Of the 187, 183 were followed at 12 weeks. INTERVENTIONS: Measurement of the IOP with the Tono-Pen before therapy was started and 12 weeks after therapy was started. OUTCOME MEASURE: IOP. RESULTS: No significant rise in IOP was observed. No patient had a rise in IOP greater than 4 mm Hg. CONCLUSIONS: Although isolated case reports indicate a definite risk of glaucoma in the presence of inhaled steroid therapy, the risk appears to be small.
BACKGROUND: Primary juvenile glaucoma is a rare form of glaucoma that typically affects individuals between 3 and 20 years of ages and is inherited as an autosomal dominant trait. One gene responsible for this condition has been localized to the 1q21-q31 region of chromosome 1. To investigate the clinical features of this form of glaucoma, the authors have examined the affected members of five pedigrees demonstrating genetic linkage to the 1q21-q31 locus. METHODS: Clinical characterization of 23 affected patients was performed. Genetic linkage to the 1q21-q31 locus was confirmed by segregation of the disease trait in each pedigree with genetic markers located in the 1q21-q31 region. RESULTS: The clinical features of affected members of the five pedigrees presented are generally homogeneous. The average age of diagnosis was 18.5 years (range, 5-30 years), and the average initial intraocular pressure was 38.5 mmHg (range, 30-53 mmHg). Eighty-seven percent of affected individuals were myopic and 83% of affected individuals required surgical treatment for glaucoma. There were no uniformly associated systemic or ocular conditions. One possible nonpenetrant carrier was identified and a difference in phenotypic expression of the presumed disease gene was observed in a pair of affected monozygotic twins. We also identified two pedigrees with juvenile glaucoma and three pedigrees affected by the pigment dispersion syndrome that are not genetically linked to the 1q21-q31 region. CONCLUSION: The form of juvenile glaucoma caused by a gene located in the q21-q31 region of chromosome 1 is generally phenotypically homogeneous. The severe elevation of intraocular pressure typically seen in affected patients suggests the product of the predisposing gene may participate in the outflow function of the eye.
PURPOSE: The anterior segment findings of children with glaucoma following pediatric cataract extraction were studied to determine the mechanism of this complication. METHODS: The clinical records of 65 children with glaucoma cared for by the author were studied. Patients with bilateral lensectomy followed by bilateral glaucoma, bilateral lensectomy followed by unilateral glaucoma, and unilateral lens surgery followed by glaucoma were identified and studied. RESULTS: It was determined that vitreous cutting instruments were used for 80% of the lensectomy procedures, with 77% of the lens procedures done in the first year. Eighty-seven percent of the patients were recognized to have glaucoma two or more years after their lensectomy. Preoperative gonioscopy revealed no consistent angle defect, while postoperative gonioscopy revealed a near constant (96%) but variable angle defect characterized by blockage of the trabecular meshwork by an acquired repositioning of the iris against the posterior trabecular meshwork, associated with abnormal pigmentation and synechia formation. CONCLUSION: The results reported document the development of a characteristic acquired filtration angle deformity in children with glaucoma following early lensectomy frequently associated with significant residual lens tissue and unassociated with evidence of chronic anterior segment inflammation.
Vertebrate Pax proteins share a conserved 128-amino-acid DNA-binding motif, the paired domain. The PAX6 gene, which is mutated in the murine Small eye and human aniridia developmental defects, also encodes a second protein with a 14-amino-acid insertion in the paired domain. This protein, which arises by alternative mRNA splicing, exhibits unique DNA-binding properties. Unlike other paired domains, which bind DNA predominantly by their amino termini, the extended Pax6 paired domain interacts with DNA exclusively through its carboxyl terminus. This property can be stimulated by deletion of 30 amino-terminal residues from the Pax6 or Pax2 paired domains. Thus, the insertion acts as a molecular toggle to unmask the DNA-binding potential of the carboxyl terminus. The functional nonequivalence of the two Pax6 proteins is underscored by a T-->C mutation at position -3 of the alternative splice acceptor site that changes the ratio of the two isoforms and causes a distinct human ocular syndrome.
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To assess the use of drainage implants in pediatric patients with glaucoma refractory to conventional medical and surgical therapy, we retrospectively reviewed 20 consecutive eyes in children 10 years of age or younger treated with 16 Molteno (three of which were removed and replaced with second Molteno shunts) and seven Baerveldt implants. The age of the patients ranged from 1 month to 10 years (mean, 3 years). The patients had undergone a mean of two previous failed glaucoma procedures (range, one to six). The mean intraocular pressure (IOP) prior to drainage tube implantation was 37 +/- 4 mm Hg, compared with a mean of 18 +/- 6 mm Hg following surgery, with average postoperative follow up of 25 months (range, 8 to 41 months). The overall success, defined as IOP < or = 21 mm Hg without further surgical therapy, was 80%. Postoperative glaucoma medications were required in 75% of patients. There were 23 complications, one of which resulted in decreased visual acuity. These findings demonstrate that drainage tube implants can be effective in lowering IOP in uncontrolled pediatric glaucomas. Patients often require postoperative glaucoma medications and close monitoring for complications.
Aniridia is a semidominant disorder in which development of the iris, lens, cornea and retina is disturbed. The mouse mutation Small eye (Sey), which has been proposed as a model for aniridia, results from defects in Pax-6, a gene containing paired-box and homeobox motifs that is specifically expressed in the developing eye and brain. To test the role of PAX6 in aniridia, we isolated human cDNA clones and determined the intron-exon structure of this gene. PAX6 spans 22 kilobases and is divided into 14 exons. Analysis of DNA from 10 unrelated aniridia patients revealed intragenic mutations in three familial and one sporadic case. These findings indicate that the human aniridia and murine Small eye phenotypes arise from homologous defects in PAX6.
Multinucleate tumor cells were observed in a case of a retinal tumor suspected to be a retinoma (retinocytoma). On electron microscopy, these cells had characteristics of retinoblastoma. Similar cells were observed in an irradiated model of retinoblastoma grown in a nude mouse. We suggest that the presence of these cells indicates differentiation and/or regression of the tumor.
A 5-day-old female patient was found to have large hereditary retinoblastomas in the posterior pole of each eye. The patient received radiation treatment over a 39-day period, with each retina receiving 4600 rad. Two weeks after the complete treatment the tumours had regressed to approximately one-quarter of their original size. By 14 weeks following completion of radiotherapy the patient had developed in each eye extensive iris neovascularisation with progressive closure of the filtration angles, secondary glaucoma, and retinal detachments resulting from fibrovascular proliferation on the retinal surface. Radiosensitivity studies were from separate conjunctival biopsies obtained before and after radiation. These showed a D0 (calculated survival curve parameters, defined in the Methods section) in the exponential growth phase of 110 prior to radiation and a postirradiation exponential growth phase D0 of 70. Karotype studies showed several chromosomal abnormalities following radiotherapy. The clinical course and pathology findings are thought to represent an unusually severe orbital and ocular response to radiation therapy. These findings are consistent with our hypothesis that some patients with hereditary retinoblastoma may have a defect in the accumulation repair of x-irradiation induced DNA damage.
Repetitive gonioscopy of children with congenital aniridia confirms the presence of an angle abnormality which can be progressive and cause glaucoma. This abnormality features obstruction of the trabecular meshwork by variable mixtures of anterior migration of the peripheral iris and thickening of the uveal meshwork associated with a vascular net over exposed trabecular meshwork adjacent to the anterior edge of the iris. Preliminary results of prophylactic gonio-surgery in 28 eyes of 16 children with an average age of 4 years was reported. This surgery was performed without complication and produced a permanent exposure of the trabecular meshwork to the anterior chamber for an average of 8 circumferential hours, if two procedures were performed. Preliminary results suggest a stabilization of eye pressures at least through childhood and encourage the continuation of these prophylactic operations on selected eyes with congenital aniridia. Therapeutic goniotomy for established acquired glaucoma in congenital aniridia cannot be relied on, but may be a benefit for early detected cases or for glaucoma associated with aniridia in infancy.
We present nine patients with unilateral congenital ectropion uveae (hyperplasia of the iris pigment border), iris hypoplasia, characteristic gonioscopic findings, and glaucoma. A majority of these patients also demonstrated mild ptosis. In none of these patients were there any associated systemic abnormalities. The apparent ectropion uveae results from spread of the iris pigment epithelium beyond the iris ruff and onto the anterior surface of the iris. In two patients with this abnormality, histopathologic and electron microscopic findings are presented. All patients with congenital ectropion uveae should be carefully examined periodically to detect glaucoma.
Six cases of the melanotic neuroectodermal tumor of infancy, including light and electron microscopic findings, are presented. The tumor, now believed to originate from neural crest, is usually cured by wide excision; however, malignant cases have been reported. Histopathologically, this lesion resembles neural retina and retinal pigment epithelium. It may involve the orbit but most frequently occurs in the maxilla. One case presented involved the orbit, another the anterior fontanelle, and four presented in the maxilla.
Three children (two girls and one boy) with bilateral retinoblastoma each developed a presumed rhegmatogenous retinal detachment in one eye. All three eyes had previously received radiation and cryotherapy. In each case the retinal detachment responded promptly to conventional surgical methods via scleral buckling in the area of treated retinoblastoma and presumed retinal break. All three eyes have retained useful vision for follow-up periods of 3.5 to 12 years.
We studied two children who died of suspected familial erythrophagic lymphohistiocytosis. The first child, a 7-year-old boy, had fever, diffuse pulmonary infiltrates, bilateral choroidal effusions, diabetes insipidus, and marked meningitis with increased cerebrospinal fluid protein. Ocular histologic studies disclosed diffuse choroidal infiltrates consisting of atypical mononuclear cells with foamy cytoplasm. Similar histologic changes were seen in the lungs, liver, brain, and kidneys. The second child, the 5-year-old male cousin of Patient 1, had fever, hepatosplenomegaly, pulmonary infiltrates, and cerebrospinal fluid pleocytosis. Histologic changes were similar to those in the first case, but viral particles of the herpes simplex virus group were noted in brain tissue as well. The findings of virus particles in this histiocytic proliferative disease suggested a defect in the inflammatory response in these patients.
Thirty-four patients with childhood glaucoma who had difficult management problems in spite of conventional glaucoma medications were entered into an investigational protocol designed at a time when timolol was not available commercially. Since controlled studies in adult glaucoma had demonstrated the efficacy of timolol, a trial of the drug in these difficult childhood cases seemed justified. The study was approved by the Human Studies Committees of the Children's Hospital Medical Center and the Massachusetts Eye and Ear Infirmary, Boston, MA. These children have been followed for periods up to 2 1/2 years. In general, timolol was added to the maximum tolerated medical therapy. Definite improvement was noted in 10 patients, modest or equivocal improvement in 11, and in 13 no substantial benefit to their course occurred when timolol was added. youngsters over 5 years of age showed an average reduction in resting pulse rate of 6 beats/minute similar to that previously found in adult patients. Under 5 years of age no change in the resting pulse rate could be detected. One patient was discontinued from timolol for a possible adverse effect. The experience particularly in very young children is still quite limited, but the beneficial effects observed warrant further evaluation.