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CHROMOSOMAL ABNORMALITIES ASSOCIATED with CYCLOPIA and SYNOPHTHALMIA* by Rufus 0

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CHROMOSOMAL ABNORMALITIES ASSOCIATED with CYCLOPIA and SYNOPHTHALMIA* by Rufus 0 CHROMOSOMAL ABNORMALITIES ASSOCIATED WITH CYCLOPIA AND SYNOPHTHALMIA* BY Rufus 0. Howard, MD, PhD INTRODUCTION CYCLOPIA IS THE MOST GROTESQUE DEVELOPMENTAL ABNORMALrrY IN OPHTHAL- mology. The term is commonly used to describe either the abnormality of true cyclopia, in which a single median eye is the only ocular structure present, or synophthalmia, in which two globes are partially fused in a median position. The cause for this malformation has been obscure. Familial occurrence, occurrence in twins, and in consanguineous marri- ages fias been documented and would be consistent with a single gene abnormality. However, cyclopia has been produced experimentally in numerous species following exposure to various teratogenic agents, and this has been interpreted as evidence for an environmental cause of cyclopia. In recent years, several isolated case reports of cyclopia in humans have been associated with abnormal chromosomes. In this report, eight cases of human cyclopia and synophthalmia are reported with chromosome studies. Five had abnormal chromosomes; one had systemic and ocular abnormalities consistent with D trisomy (although chromosome results are not available); and two had normal chromosomes. A wide spectrum of ocular histopathologic changes were observed. In addition, the published literature on chromosomal ab- normalities in cyclopia is reviewed. Most cases of human cyclopia can be attributed to a chromosomal aberration. While multiple etiology cannot be excluded, evidence will be presented to support the interpretation that even "familial" cases of cyclopia, and cyclopia attributed to environmental agents are not in- consistent with chromosomal errors in the affected individuals. *From the Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Conn. and the Division of Ophthalmology, University of Connecticut Medical School, Farmington, Conn. TR. AM. OPHTH. Soc., vol. LXXV, 1977 506 Howard CASE REPORTS CASE 1 A black female infant was delivered by cesarean section, because of fetal dis- tress, at 36 weeks gestation in New Haven, Conn. The infant had no spon- taneous respirations at birth: the Apgar was 1 at one and five minutes. Multiple congenital abnormalities were apparent at birth (Fig. 1A), including syn- ophthalmia in the middle of the forehead with a proboscis above the eye, low set ears, and postaxial hexadactyly of both hands and both feet. The child was pronounced dead 10 minutes following delivery. Blood was obtained for chromosome studies before death. The 23-year-old, Type A, Rh positive mother had one normal living child. POST-MORTEM EXAMINATION This 1460 gm infant was 42.5 cm long and had a head circumference of24 cm. A 20 x 7 mm nasal proboscis with imperforate opening was located above the median diamond shaped eye socket which measured 15 mm x 9 mm. The mouth was 29 mm wide. Several facial bones, especially those associated with the nose, were missing. Cardiac anomalies in- cluded left ventricular hypoplasia, widely-patent ductus arteriosus, widely- patent foramen ovale, dilated right atrium, and dilated proximal por- tion of the ascending aorta. A single umbilical artery connected with the left common iliac artery. An accessory spleen was present in the phreno- cocolonic ligament. The 74 gm brain was holoprosencephalic. The cerebral hemispheres were not cleaved rostrally. Posteriorly, there was partial cleavage with formation of symmetrical occipital lobes. The brain-stem and cerebellum appeared normal. No optic or olfactory nerves or tracts were seen at the base of the brain. Coronal sectioning of the brain confirmed the presence of a holosphere; the cortex and white matter were over 1 cm thick. Microscopic examination of all nonocular tissues were normal except for: degenerative cystic dilatation of thyroid follicles; accessory splenic tissue in the tail of the pancreas; immature ovarian follicles with para- ovarian simple cysts. In the brain, rather distinct lamination of the cortex was present with six identifiable layers. A rostral ventricular cavity had not developed, but the aqueduct and fourth ventricle were identified. The meninx primitiva was continuous with the leptomeninges rostrally and caudad. It was not possible to identify any basal ganglion or midbrain structure on serial section. The leptomeninges over the cerebellar hemispheres were markedly congested. Cyclopia and Synophthalmia 5507 FIGURE 1 Case 1. A: This female infant with synophthalmia has 13 trisomy (47,XX, +13). B: The enucleated synophthalmic eyes are small. Only a single optic nerve is present. c: All layers of the cornea are abnormal. The superficial stroma is vascularized. D: The iridocorneal angle in the synophthalmic eye is immature. E: The lens epithelium extends posteriorly to completely line the capsule. The tunica vasculosa lentis persists. F: Retinal dysplasia, gliosis and intraretinal hemorrhage were present in the synophthalmic eye. GROSS OCULAR EXAMINATION The orbital contents consisted oftwo fused globes (Fig. IB), and measured 24 x 18 x 14 mm. The right cornea measured 4 x 2 mm, and was separated from the 3 x 2 mm left cornea by a segment of scleral tissue. The corneas were hazy and the anterior chambers and angle structures were not identified on gross examination. Only a single optic nerve was evident. After the synophthalmic globes were sectioned in a horizontal plane, a 508 Howard septum was observed to separate the two partially fused globes. Two separate corneas, anterior chambers, irides, and lenses were present. The lenses were partially opaque and spherical. Remnants suggestive of ciliary body were identified. The retina appeared redundant and folded, and the disc was not visualized. The sclera of the two globes was fused medially. MICROSCOPIC OCULAR EXAMINATION The junction of the globes and surface epithelium was keratinized with some rete peg formation. The corneal epithelial cells had an irregular arrangement (Fig. 1C). Bowman's membrane was not identified. The corneal stroma was thick and vascularized and the lamellae were irregular. Descemet's membrane was poorly defined but intact. A peripheral area of coiled Descemet's membrane was present. The endothelium was several cell layers thick and had pigment granule inclusions. The anterior chambers were filled with eosinophilic material and erythrocytes. In both eyes the iridocorneal angles were incompletely formed and the trabecular meshwork was not well defined (Fig. 1D). The iris remained attached to Descemet's layer in peripheral areas. The iris stroma was a dense mesenchymal tissue with pigment containing cells, and the iris appeared necrotic. At the pupillary margin, the iris was folded posteriorly. In the ciliary body, the stroma and ciliary muscles were very cellular and contained a few extravasated red blood cells. The ciliary processes were of variable length, and in places, extopic retina was attached. A per- sistent tunica vasculosa lentis surrounded a thickened lens capsule (Fig. IE). Within the lens, there was posterior migration of epithelial cells, occasional bladder cells, and Morgagnian globules. The lens cortical fibers showed areas ofdegeneration and the nuclei were sclerotic. Hemor- rhage separated the detached, dysplastic retina from the retinal pig- ment epithelium. There was loss of the normal retinal architecture with extensive dyplastic retina formation, gliosis, and intraretinal hemor- rhage (Fig. 1F). A few ganglion cells were seen. A mass of loosely arranged cells, probably representing primary vitreous, was identified in the vitreous cavity. The retinal pigment epithelium was necrotic in areas. The choroid was highly cellular with areas of intrachoroidal hemorrhage. A single optic nerve was seen coursing through the attached orbital fat. Cyclopia and Synophthalmia 509 DIAGNOSIS Synophthalmia Abnormal cornea (abnormal epithelium, Descemet's, and endo- thelium; absent Bowman's layer; vascularized stroma) Immature iridocorneal angle Cataract Persistent tunica vasculosa lentis and primary vitreous Retinal detachment and retinal dysplasia Choroidal hemorrhage Fused optic nerve CHROMOSOMAL EXAMINATION Peripheral leucocytes were cultured and chromosomes were harvested and stained by a Giemsa banding technique. The modal chromosome count was 47,XX, +13 (in 12 cells). An apparently random artifactual chromosomal loss was seen in four cells: 46,XX, +13, - (9, 19, or 20). CASE2- A female infant was stillborn in London, England at 38 weeks gestation following induced labor. Polyhydramnios was recognized at 34 weeks gestation. The 2690 gm cyclopic girl was not macerated; her crown-heel length was 50 cm; the crown-rump length was 31 cm; and the head circumference was 32 cm. A third fontanelle was present. A trunk-like probiscis protruded above a single diamond-shaped central eye opening. No gross tissue was apparent in this space. The ears were low set and the mouth was small. Mild bilateral talipes equino- varus was present. The mother was 27 years old, and she had blood Type A, Rh positive. POST-MORTEM EXAMINATION The 63 gm brain was grossly malformed; the anterior fossae were small and fused. Prominent blood vessels covered the surface ofthe cerebrum. Most of the cranial cavity was occupied by a very thin walled cyst which contained clear fluid. The centrally situated cerebrum was represented by a crescent of cerebral tissue which occupied the anterior third of the cavity and was continuous with the thin cyst wall. No olfactory nerves were present, and the posteriorly placed central
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