Robert A. Petersen

Oncogenic Point Mutations in the Human Retinoblastoma Gene: Their Application to Genetic Counseling

Mutations of the retinoblastoma gene, most of which cannot be detected by conventional Southern blotting, are known to cause both the nonhereditary and hereditary forms of retinoblastoma and have been implicated in the development of other cancers. Nonhereditary retinoblastoma is caused by a somatic mutation. Hereditary retinoblastoma is caused by a germ-cell mutation, most often a new one, and thus there is usually no family history of the disease. Unlike patients with the nonhereditary disease, those with the hereditary form are at risk for additional retinoblastomas, and their progeny are at risk for the tumors. We used a sensitive technique of primer-directed enzymatic amplification, followed by DNA sequence analysis, to identify mutations as small as a single nucleotide change in tumors from seven patients with simplex retinoblastoma (with no family history of the disease). In four patients the mutation involved only the tumor cells, and in three it involved normal somatic cells as well as tumor cells but was not found in either parent; thus, these mutations appeared to be new, germ-cell mutations. In addition, we found point mutations in cells from a bladder carcinoma, a small-cell carcinoma of the lung, and another retinoblastoma. We conclude that the technique that we have described can distinguish hereditary from nonhereditary retinoblastoma and that it is useful in risk estimation and genetic counseling.

Homozygosity of Chromosome 13 in Retinoblastoma

We studied the frequency of chromosome 13 homozygosity in tumor tissue obtained directly from eyes harboring retinoblastomas. The data indicate that approximately half of all retinoblastomas are homozygous for large portions of 13q, that the homozygosity occurs in vivo and not as an event secondary to culture of the tumor cells, that chromosome 13 homozygosity is not correlated with the degree of histopathologic differentiation of the tumor, and that the homozygosity occurs in both sporadic and hereditary retinoblastomas. The development of chromosome 13 homozygosity may represent a fundamental event in the oncogenesis of a considerable number of retinoblastomas. This finding may have implications for the genetic counseling of patients with hereditary retinoblastoma. It may also be important in understanding the mechanism of oncogenesis of other tumors, especially hereditary tumors.

The natural course of congenital obstruction of the nasolacrimal duct.

In order to establish the rate of spontaneous resolution of congenital obstruction of the nasolacrimal duct, 50 infants, referred from a local pediatric group practice over a period of five years, were followed from the time of first symptoms until 8 to 13 months of age. Among the 50 infants, 65 nasolacrimal ducts were blocked and 58 ducts in 44 patients opened spontaneously. Only seven ducts in six patients required probing for relief of the obstruction. During the same period another seven patients from various referral sources were seen because of noninflammatory swelling of the lacrimal sac at birth. These patients were also found to have nasolacrimal duct obstruction, but early surgical intervention was required in six of the seven patients to relieve the distention of the sac.

Cycloplegic Refractions in Infants and Young Children

We studied groups of normal infants and infants with amblyopia and esoropia to determine the incidence of infantile astigmatism. Under cycloplegia, 19% of normal infants had astigmatism; this was at least twice the incidence in adults, but less than one-hale that found by noncycloplegic refractions of infants. During the first three postnatal years the incidence of astigmatism and distributions of spherical equivalents and anisometropia did not distinguish normal patients from most of those with esotropia and amblyopia.

The Relation of Myopia and Astigmatism in Developing Eyes

The relation of astigmatism and myopia was analyzed in 298 myopic children, ages birth to 10 years. The mean spherical equivalent, determined by cyclopentolate retinoscopy, for the entire group was--2.9 diopters and did not change significantly with age. However, in 3-year-old children and younger, myopia progressed in eyes with greater than or equal to 1 diopter of cylinder and tended to increase through age 8 years in those having greater than or equal to 3 diopters of cylinder. Also, astigmatic errors greater than or equal to 1 diopter, especially of oblique orientation, were associated with higher degrees of myopia than nonastigmatic errors. These data from myopic children suggest that uncorrected astigmatism during a period of visual immaturity influences the course of myopia. Thus, naturally occurring astigmatic errors, that are frequent among infants and young children, appear to have a role similar to the vision blurring perturbations that trigger the development of myopia in young animals. Ascertainment and full correction of these refractive errors in young children may be important in assuring the best possible vision.

Second nonocular tumors among survivors of retinoblastoma treated with contemporary photon and proton radiotherapy

The leading cause of death among patients with hereditary retinoblastoma is second malignancy. Despite its high rate of efficacy, radiotherapy (RT) is often avoided due to fear of inducing a secondary tumor. Proton RT allows for significant sparing of nontarget tissue. The current study compared the risk of second malignancy in patients with retinoblastoma who were treated with photon and proton RT.

Outcome of Treatment for Bilateral Congenital Cataracts

The outcome of treatment for bilateral congenital cataracts was studied retrospectively in a group of 51 patients. Two major categories of lens opacities were identified. In the first category, the opacities were extensive and visual impairment was evident early in the first year. These cataracts often occurred in eyes with small corneal diameters and poorly dilating pupils. Postoperative strabismus was nearly universal; nystagmus developed in over 50%; and late onset open-angle glaucoma developed in 8 of the 29 patients studied. Early surgery did not seem to abort the development of nystagmus in this group of patients. In the second category, the lens opacities were partial, often lamellar in configuration, and visual impairment was less severe. Surgery was usually performed after 3 years of age, with good visual results if the opacities were symmetrical and there was no nystagmus. No deprivation amblyopia developed in this group, even when surgery was delayed into the second decade. Strabismus developed postoperatively in about a third, but so far, no delayed open-angle glaucoma has been identified.

Optic Disc Drusen in Children

Forty children with pseudopapilledema due to optic disc drusen (31 bilateral, nine unilateral) were studied retrospectively to characterize the early natural history of this condition. The average age at the first examination was 10.2 years (range 3.6 to 19.5 years), and the mean follow-up period was 44 months. Discrete hyaline bodies or papillary calcifications were first noted in one or both eyes with pseudopapilledema at a mean age of 12.1 years in 38 of 40 cases. Decreased visual acuity due to drusen occurred in only one eye due to subretinal neovascularization. Visual fields obtained in 35 eyes (21 patients) with pseudopapilledema showed an enlarged blind spot (9), an inferior arcuate/sector/or altitudinal defect (6), or both (3) in 18 eyes. Our study suggests that discrete papillary calcifications or hyaline bodies frequently emerge and visual field deficits are commonly detectable in the second decade of life in patients with pseudopapilledema due to optic disc drusen.

Heterochromia and horner syndrome associated with cervical and mediastinal neuroblastoma

Index patient. O. H. was referred to the Sidney Farber Cancer Center and Childrens Hospital Medical Center at the age of 15 months~ Two months prior to admission, his parents noted a nontender, nonpainful mass, approximately 1 cm in diameter, in the left side of the neck. A biopsy revealed the presence of metastatic neuroblastoma to the left cervical nodes, and a mass ,with stippled calcification in the left supramediastinal area was demonstrated by chest radiograph. The patient was born with a congenital left Homer syndrome which gradually improved as he grew older. Concurrently,

Bacterial subretinal abscess: a case report and review of the literature.

PURPOSE To report a case of Klebsiella subretinal abscess with a successful visual outcome with treatment and to review the literature pertaining to focal intraocular infection in bacterial endophthalmitis. METHODS Clinical data including medical history, findings on physical examination, blood cultures, and an abdominal computed tomographic scan were collected in a 32-year-old man with Klebsiella sepsis, liver abscesses, and a focal subretinal abscess. Ocular data including visual acuity, fundus photographs, fluorescein angiography, and ultrasound were evaluated, as were results of culture and histopathologic studies. RESULTS Despite immediate intervention, including vitreous tap and intravitreal antibiotics, the eye deteriorated, with enlargement of the abscess. A pars plana vitrectomy was performed in which the subretinal abscess material was removed after an extensive retinectomy of the involved area in association with an endophotocoagulative barrier and intravitreal amikacin without gas or oil tamponade. Culture confirmed Klebsiella subretinal infection. A retinal detachment occurred 1 month postoperatively and was successfully repaired. Visual acuity was 20/30 and has remained stable for 14 months. CONCLUSION Klebsiella endophthalmitis with subretinal abscess formation is a rare but devastating ocular condition. In the present case, prompt intervention with extensive retinectomy, complete abscess excision, and intravitreal antibiotic therapy resulted in unprecedented visual recovery.