Journal of Pediatric Ophthalmology and Strabismus

Pathologic Features of the Eye in Trisomy 9

Joseph Ginsberg, MD; S Soukup, PhD; Edgar T Ballard, MD

Abstract

Chromosome 9 seems to be particularly prone to structural anomalies, especially pericentric inversions, and to partial trisomies. Trisomy of the short arm, a clinically identifiable syndrome compatible with a normal life expectancy, appears to be the most common partial trisomy in humans.1 Full trisomy 9 generally results in abortion. The mosaic form allowsdevelopment to term and occasionally survival." In approximately twelve live-born infants with full trisomy 9, nine" were found to be mosaic and three*'"' i: exhibited a questionably complete (lymphocytes only) trisomy.

Delineation of a trisomy 9 syndrome is emerging. Among the most common findings are microcephaly, and/or brain malformation, abnormalities of the cranial sutures with widely patent fontanelles, facial asymmetry, deeply -set eyes, pouched cheeks with "chipmunklike" face, low hairline, micrognathia, low-set malformed ears, broad-based nose with bulbous tip, small mouth, down- turned at the corners, long philtrum, higharched palate, congenital heart disease, skeletal and genitourinary anomalies, hypotonia, abnormal palmar creases, mental retardation and failure to thrive.

The ocular findings in mosaic trisomy 9 have included deeply-set eyes, small, slightly mongoloid palpebral fissures, telecanthus or hypertelorism, microphthalmos, alacrimia, blepharoptosis, epicanthus and strabismus. An opportunity to examine the eyes of a neonate with mosaic trisomy 9 prompted us to study the pathologic features and compare them with those described in other developmental disorders.

Case Report

A white girl weighing 1740 gm and measuring 43 cm in length was born to a 29-year-old gravida 1 mother after an uneventful full-term gestation. Apgar scores were 1 and 3 at 1 and 5 minutes, respectively. Anomalies recorded at birth included slight brachycephaly (circumference = 31 cm), slight telecanthus, small palpebral fissures with deeply-set eyes, a left cataract and/or corneal opacity, dilated fixed pupils, small inferiorly placed ears, a broad somewhat bulbous nose, long philtrum, small mouth, down-turned at the corners, micrognathia, midline cleft involving the hard and soft palate and a webbed neck. A deviated larynx was associated with a left diaphragmatic hernia; radiologically aeration was absent in the left lung and minimal in the right one. Laxity of all joints accompanied dislocated hips and shoulders. Underdeveloped genitalia included an absent clitoris.

Theinfant experienced continuous respiratory distress with a falling blood pressure and pulse rate. In spite of resuscitative efforts, death resulted from cardiorespiratory arrest four hours after birth.

At necropsy, there was a large defect in the left diaphragmatic leaf through which the left lobe of the liver, stomach, most of the intestinal tract, pancreas and spleen herniated into the left thoracic cavity. The collapsed left lung was markedly hypoplastic (4.5 gm) and the right lung (9.5 gm) was compressed by a tension pneumothorax. The small (12 gm) heart exhibited an atrial septal defect (6 mm) that replaced the foramen ovale. Moderate dilatation of the left ureter was associated with hydronephrosis and subcortical cysts. The brain (293 gm) displayed a slightly simplified gyral pattern. Moderate ventricular dilatation (posterior and temporal horns) was associated with subependymal cysts along the floor of the lateral ventricles and periaqueductal ependymal rosettes.

Some of the corneolenticular changes seen here were similar to those noted in association with agenesis of other ocular and extraocular structures and with Lowe's syndrome. A thinning of the posterior corneal stroma and proliferation of corneal endothelium occurred with aplasia of the optic nerve and aniridia.26 A central defect involving keratocytes, endothelium and Descemet's membrane was associated with renal agenesis (Potter's syndrorne).27 A marked thinning or dehiscence of the posterior lens capsule is characteristic of the oculocerebrorenal (Lowe) syndrome.

The overall findings in our patient resembled those in other mosaic trisomy 9 cases. Cerebral ventricular dilatation2,9,10 and cyst formation (cerebral ependymal,' renal,6 ciliary…

Chromosome 9 seems to be particularly prone to structural anomalies, especially pericentric inversions, and to partial trisomies. Trisomy of the short arm, a clinically identifiable syndrome compatible with a normal life expectancy, appears to be the most common partial trisomy in humans.1 Full trisomy 9 generally results in abortion. The mosaic form allowsdevelopment to term and occasionally survival." In approximately twelve live-born infants with full trisomy 9, nine" were found to be mosaic and three*'"' i: exhibited a questionably complete (lymphocytes only) trisomy.

Delineation of a trisomy 9 syndrome is emerging. Among the most common findings are microcephaly, and/or brain malformation, abnormalities of the cranial sutures with widely patent fontanelles, facial asymmetry, deeply -set eyes, pouched cheeks with "chipmunklike" face, low hairline, micrognathia, low-set malformed ears, broad-based nose with bulbous tip, small mouth, down- turned at the corners, long philtrum, higharched palate, congenital heart disease, skeletal and genitourinary anomalies, hypotonia, abnormal palmar creases, mental retardation and failure to thrive.

The ocular findings in mosaic trisomy 9 have included deeply-set eyes, small, slightly mongoloid palpebral fissures, telecanthus or hypertelorism, microphthalmos, alacrimia, blepharoptosis, epicanthus and strabismus. An opportunity to examine the eyes of a neonate with mosaic trisomy 9 prompted us to study the pathologic features and compare them with those described in other developmental disorders.

Case Report

A white girl weighing 1740 gm and measuring 43 cm in length was born to a 29-year-old gravida 1 mother after an uneventful full-term gestation. Apgar scores were 1 and 3 at 1 and 5 minutes, respectively. Anomalies recorded at birth included slight brachycephaly (circumference = 31 cm), slight telecanthus, small palpebral fissures with deeply-set eyes, a left cataract and/or corneal opacity, dilated fixed pupils, small inferiorly placed ears, a broad somewhat bulbous nose, long philtrum, small mouth, down-turned at the corners, micrognathia, midline cleft involving the hard and soft palate and a webbed neck. A deviated larynx was associated with a left diaphragmatic hernia; radiologically aeration was absent in the left lung and minimal in the right one. Laxity of all joints accompanied dislocated hips and shoulders. Underdeveloped genitalia included an absent clitoris.

Theinfant experienced continuous respiratory distress with a falling blood pressure and pulse rate. In spite of resuscitative efforts, death resulted from cardiorespiratory arrest four hours after birth.

At necropsy, there was a large defect in the left diaphragmatic leaf through which the left lobe of the liver, stomach, most of the intestinal tract, pancreas and spleen herniated into the left thoracic cavity. The collapsed left lung was markedly hypoplastic (4.5 gm) and the right lung (9.5 gm) was compressed by a tension pneumothorax. The small (12 gm) heart exhibited an atrial septal defect (6 mm) that replaced the foramen ovale. Moderate dilatation of the left ureter was associated with hydronephrosis and subcortical cysts. The brain (293 gm) displayed a slightly simplified gyral pattern. Moderate ventricular dilatation (posterior and temporal horns) was associated with subependymal cysts along the floor of the lateral ventricles and periaqueductal ependymal rosettes.

FIGURE 1: Giemsa banded karyotype of cell line showing 47,XX,*9. Arrow indicates extra number 9 chromosome.

FIGURE 1: Giemsa banded karyotype of cell line showing 47,XX,*9. Arrow indicates extra number 9 chromosome.

Cytogenetic Studies: Chromosomal preparations from a blood culture showed mosaic 46.XX/47.XX.+9 in 105 cells scored. Approximately 44% metaphases showed 47 count, 53% 46, and 3% had 45 count. A Giemsa banded karyotype 47.XX.+9 is illustrated in Figure 1. A fibroblast culture also showed approximately 50% cells 46 count and 50% 47 in 19 scored. A possible 9qh+ was seen in Cbanded metaphases. Both parents had normal chromosomes and both had one possible 9qh+ chromosome.

Ocular Pathology: Both eyes and optic nerves were removed and fixed in 10% formalin. Paraffin sections (5 µ) were stained with hematoxylin and eosin, PAS and Masson's trichrome method.

Each globe measured approximately 19x19x18 mm in the three principal meridians and had a 1.5 mm optic nerve stump. A horizontal section of the right was unremarkable. In the left one an anteriorly dislocated lens seemed adherent to a central corneal opacity (Figure 2).

Microscopie: In the right eye the cornea had a thickened, edematous stroma, a hypoplastic epithelium and an irregular endothelium that exhibited duplication and nodular proliferation (Figure 3). Descemet's membrane was poorly defined and in many areas not discernible. The anteriorly displaced lens was partly surrounded by the tunica vasculosa. Its capsule was redundant anteriorly and thinned posteriorly in relation to epithelial proliferation and early cortical liquefaction. The markedly hypoplastic iris exhibited slight ectropion uveae and incomplete separation from the trabecular mesh work. Hyperplasia of ciliary epithelium was either solid, cystoid or in the form of strands that reached the posterior iris surface. Nasally the retina contained small foci of dysplasia with neuroglial proliferation as well as hemorrhage and an extension onto the pars plana (Figure 4). Slight neuronal hyperplasia occurred in the temporal retina.

The left cornea, flatter than in the right eye, was markedly indented by a somewhat spheroidal lens (Figure 5). In relation to the central corneal opacity, Bowman's membrane was either markedly thickened, indistinct or shifted posteriorly. Stromal lamellae were edematous and irregularly arranged and corneal endothelium and Descemet's membrane were absent. Peripherally the cornea exhibited an atrophic endothelium, an indistinct Descemet's membrane, and early degeneration of keratocytes. Thinning or dihiscence of the anterior and posterior lens capsule accompanied liquefaction of the adjacent cortex mainly posteriorly Figure 5). Anterior displacement of the hypoplastic iris and elongated ciliary processes resulted in apposition or adhesion with an immature trabecular meehwork (Figure 5). Connecting strands between hyperplastic ciliary epithelium and iris were more marked than in the right eye (Figure 6). Retinal changes were comparable to those in the right eye. The sclera thickened and contained foci of hematopoiesis posteriorly.

Discussion

Since ocular pathologic studies have not been reported in mosaic trisomy 9, the significance of our findings is unknown. All of them occur (singly or in combination) in other cytogenetic and non-chromosomal disorders.

The ocular lesions that involved the anterior segment were most striking and reflect both immaturity and dysgenesis. There were similarities to Peters' anomaly," particularly in the left eye. A hyperplastic corneal endothelium with virtual absence of Descemet's membrane (right eye) exemplifies the developmental disparity of these structures in congenital corneal opacities, including Peters' anomaly.13

A keratolenticular adhesion, rarely described in fetuses11 or postnatally,15-18 may be bilateral15,18 or separate spontaneously" and is associated with other ocular abnormalities including Peters' anomaly,18 marked iris hypoplasia,15 congenital glaucoma," dysplasia of the posterior segment," PHPV" and microphthalmos.17,19 Rarely studied pathologically,'" a keratolenticular adhesion may result from a failure of the lens vesicle to separate from the surface ectoderm or by secondary anterior displacement of the lens-iris diaphragm.19 In our patient a primary adhesion was suggested by the marked indentation of the posterior cornea and by the absence of a pupillary membrane or vitreoretinal mass. Its proven or presumed occurrence in trisomy 13(19) and 10(20,21) and tetraploid-diploid mosaicism" suggests that chromosomal anomalies may be etiologically involved in keratolenticular adhesion.

The marked iris hypoplasia may be considered a secondary dysgenesis, severe enough to constitute a "forme fruste" of aniridia. Both mesodermal and ectodermal layers were rudimentary although the latter was comparatively better developed. Itis of interest that iris anomalies (coloboma, heterochromia) occur in trisomies of other C group (7(23) and 8(24) chromosomes and that nasal displacement of the pupil is common in pure 9p trisomy.

The embryologie and pathogenetic relationship between congenital corneal defects, lens abnormalities and iris stromal hypoplasia is debatable. Defective separation of the formed lens from the cornea, as in our patient, reflects an abnormality of the mesodermal migrations which form successively the corneal endothelium and its derivative Descemet's membrane, the corneal stroma and the iris stroma. Whether incomplete separation of the lens is the main cause of other malformations in the anterior segment is not clear. Anomalies of the anterior segment similar to those in our patient have been produced experimentally with oxygen deficiency or roentgen irradiation.25

FIGURE 2: Left eye. The lens is adherent to a central corneal opacity (gross photograph × 6.5).

FIGURE 2: Left eye. The lens is adherent to a central corneal opacity (gross photograph × 6.5).

FIGURE 3: Right eye. Corneal endothelium exhibits irregularity, duplication (small arrows) and nodular proliferation (large arrow) (hematoxylin and eosin × 350).

FIGURE 3: Right eye. Corneal endothelium exhibits irregularity, duplication (small arrows) and nodular proliferation (large arrow) (hematoxylin and eosin × 350).

FIGURE 4: Right eye. Nasal retina extends approximately halfway onto the pars plana (arrow) (hematoxylin andeosin × 35).

FIGURE 4: Right eye. Nasal retina extends approximately halfway onto the pars plana (arrow) (hematoxylin andeosin × 35).

FIGURE 5: Left eye. Cornea is indented by an adherent lens. Thinning or dehiscence of posterior capsule (arrow) is associated with beginning extrusion of liquified cortex. Note marked anterior displacement of hypoplastic iris and elongated ciliary processes (hematoxylin and eosin × 16).

FIGURE 5: Left eye. Cornea is indented by an adherent lens. Thinning or dehiscence of posterior capsule (arrow) is associated with beginning extrusion of liquified cortex. Note marked anterior displacement of hypoplastic iris and elongated ciliary processes (hematoxylin and eosin × 16).

FIGURE 6: Left eye. Strands of hyperplastic ciliary epithelium (small arrows) reach posterior surface of hypoplastic iris (large arrow). Iris root is in opposition with an immature trabecular meshwork (hematoxylin and eosin × 60).

FIGURE 6: Left eye. Strands of hyperplastic ciliary epithelium (small arrows) reach posterior surface of hypoplastic iris (large arrow). Iris root is in opposition with an immature trabecular meshwork (hematoxylin and eosin × 60).

Some of the corneolenticular changes seen here were similar to those noted in association with agenesis of other ocular and extraocular structures and with Lowe's syndrome. A thinning of the posterior corneal stroma and proliferation of corneal endothelium occurred with aplasia of the optic nerve and aniridia.26 A central defect involving keratocytes, endothelium and Descemet's membrane was associated with renal agenesis (Potter's syndrorne).27 A marked thinning or dehiscence of the posterior lens capsule is characteristic of the oculocerebrorenal (Lowe) syndrome.

The overall findings in our patient resembled those in other mosaic trisomy 9 cases. Cerebral ventricular dilatation2,9,10 and cyst formation (cerebral ependymal,' renal,6 ciliary body) seem to be features of this disorder.

The ocular and extraocular anomalies in our patient may be related embryologieally and pathogenetically. Both appear to represent the effects of a dysgenesis that affected mainly mesoderm and to a lesser extent neuroectoderm and that was operational between one and five and a half months of development.

A correlation may exist between some of the ocular and extraocular anomalies in our patient. As an example, there may be an association between the broad nose and secondary mesodermal dysgenesis of the iris; these occurred together in at least three other individuals.23 If the anterior segment changes represent a form of Peters' anomaly, then extraocular defects (cardiac, genitourinary, craniofacial, skeletal) are to be expected since they are frequently associated.25

Summary

A clinical and pathologic study of a neonate with mosaic trisomy 9 revealed findings similar to those in other cases with this chromosomal anomaly. Except for deeply-set eyes and small palpebral fissures with slight telecanthus, our ocular findings have not previously been described in mosaic trisomy 9. The most striking ocular pathologic alterations involved the anterior segment and included a keratolenticular adhesion and marked iris hypoplasia. There were similarities to Peters' anomaly as well as to ocular lesions associated with aplasia of the optic nerve and Lowe's and Potter's syndrome. The ocular and extraocular anomalies in our patient appear to have resulted from a mesoectodermal dysgenesis operational between one and five and a half months of gestation.

Acknowledgments

We are indebted to Drs. A. James McAdams and Josef Warkany for review of manuscript. Joan Ann Müller, Anela Marks, Virginia Gelczis and Maureen McCarthy provided photographic and technical assistance.

References

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10.3928/0191-3913-19820701-10

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