- Email: [email protected]
The Eye in the Partial Trisomy 2q Syndrome
THE EYE IN THE PARTIAL TRISOMY 2q SYNDROME EDWARD COTLIER, M.D., HOWARD REINGLASS, M.D., AND IRA ROSENTHAL, M.D. Chicago, Illinois
Malformation syndromes include skel etal, connective tissue, and neurological morphogenetic abnormalities, many of which manifest typical facies and ocular involvement. Chromosomal defects have been found in children or young adults with malformation syndromes and in their phenotypically normal parents. 1-14 Strabismus or other external ocular signs, a part of many characteristic facies, have been found in the inherited chromosomal defects of 9p+ trisomy with translocation to chromosome 22 or chromosome 1, tri somy 14q-, trisomy 16q, and partial trisomy 6. Ocular anomalies have also been associated with small extra chromo somes in the cat's-eye syndrome, 15-17 in the syndrome described by Abbo and Zelweger,18 and in the trisomjes 13, 18, and 21. 1 9 In the latter, the chromosomal defects are not usually inherited. Two of us (I.R., H.R.)20 described a new inherited syndrome of mandibulofacial dysotosis with skeletal, genital, and ocular manifestations. These anomalies were associated with trisomy of the distal portion of the long arm of chromosome 2, resulting from translocation to the short arm of chromosome 9. Here we describe the ocular findings in the affected males of that pedigree. We also detected anoma lies of the anterior chamber angles in one carrier female. From the Departments of Ophthalmology (Drs. Cotlier and Reinglass) and Pediatrics (Dr. Rosenthai), University of Illinois Medical Center, Chica go, Illinois. Reprint requests to Edward Cotlier, M.D., Depart ment of Ophthalmology, State University of New York at Buffalo, Buffalo General Hospital, 100 High St., Buffalo, NY 14203.
METHODS
Karyotypes were prepared with Giemsa banding from peripheral lymphocytes and cephalometric roentgenograms were analyzed. Ophthalmic examination in cluded testing of visual acuity and extraocular motility, gonioscopy, ophthalmoscopy with depression of the periphery, slit-lamp examination, and Goldmann three-mirror lens examination. In selected members of the pedigree (Fig. 1), the anterior chamber angle was photo graphed. CASE REPORTS Case III-I—The proband was a mentally retarded, 5-year-old white boy with low-set ears, a beaked nose, and sparse blond hair (Fig. 2). Examination revealed undescended testes, bilateral camptodactyly of the fifth digits, and an eczematous rash with lichenified lesions on the extensor surfaces of the extremities and on the trunk. Two procedures had been carried out for closure of a congenital cleft of both hard and soft palates, but a small residual stoma remained. Karyotypes prepared from periph eral lymphocytes with G-banding revealed a pattern of 46, XY, 9p+, representing unbalanced transloca tion to the short arm of chromosome 9 (Fig. 3).
3
TL-J* I
[2
3
4
ut>
HI /
I
2
3
Fig. 1 (Cotlier, Reinglass, and Rosenthal). Family pedigree of partial trisomy 2 syndrome of craniofacial, skeletal, gonadal, and ocular abnormalities. Arrow denotes proband.
251
252
AMERICAN JOURNAL OF OPHTHALMOLOGY
Fig. 2 (Cotlier, Reinglass, and Rosenthal). I I I - l . Facial features of the proband show typical bird-like facies.
cytogenetic studies of other family members indi cated that the translocated segment was derived from the long arm of chromosome 2. Ocular examination revealed an antimongoloid slant to the palpebral fissures. Central and steady fixation was present bilaterally. Left exotropia of 16 degrees was found in the primary position of gaze and when looking up and down. The patient had chronic blepharitis of the left eye. Examination showed an externally visible, anterior displacement of Schwalbe's ring in the right eye. Gonioscopy could not be performed because of the patient's lack of cooperation. Refraction showed - 1 . 0 0 sph + 1.00 cyl x 180° in the right eye, and - 3 . 5 0 sph + 1.50 cyl x 180° in the left eye. The maculae were granular with poor foveal reflexes. The disks, irides, lenses, and pupils appeared normal in both eyes. Case IH-2—A 3-year-old younger brother of the proband died from an overwhelming infection. At autopsy, multiple abcesses were found in the brain and kidneys. He also had a congenital cleft palate, sparse blond hair, mental retardation, low-set ears, beaked nose, antimongoloid slant to the eyes, and camptodactyly of the fifth digits of each hand. Our review of a karyotype (not banded) prepared else
AUGUST, 1977
where revealed the abnormal chromosome 9, as found in the proband. A detailed ophthalmologic examination was never performed. Case III-3—The proband's 7-year-old sister had normal facial and skeletal features (Fig. 4). Visual acuity was 6/7.5 (20/25) with a +0.75 sph in each eye. The remaining examination, including gonio scopy, was within normal limits. Karyotype was 46, XX, 2 q - , 9 p + . This was an apparently balanced translocation of the distal segment of the long arm of chromosome 2 to the short arm of chromosome 9. G-banding revealed the exact location of the translo cation (Fig. 5). Case II-1—The proband's 27-year-old maternal uncle had a heart murmur, a grade 2/6 systolic ejection murmur, and undescended testicles. He had a history of seizures for which he was taking medi cation. He also had sparse blond hair, low-set ears, and a beaked nose. He walked with a distinctive, forward-leaning gait. Camptodactyly of the fifth digit was present bilaterally. Ocular examination revealed an antimongoloid slant to the palpebral fissures. Although visual acu ity could not be obtained, the patient had a central and steady fixation of the right eye and a central but wandering fixation of the left eye. Examination for ocular motility showed no heterotropia and a full range of motion of extraocular muscles. There was chronic blepharitis with crusting of both upper and lower eyelids of each eye. The conjunctivae were clear, but the corneas showed limbal scarring from previous staphylococcal ulcers. Slit-lamp examina tion of the corneas revealed a displaced and hypertrophied Schwalbe's ring bilaterally and anteriorly. We saw no increased iris processes. Both retinas had cobblestone degeneration of the inferior temporal quadrants. Chromosomal study disclosed a 46, XY, 9p + pattern. By G-banding, the extra chromatin material on the short arm of chromosome 9 was identified as a portion of the long arm of chromosome 2. Case II-2—The proband's 25-year-old mother had unremarkable skeletal and facial features except for a slightly beaked nose. Posture and gait were nor mal. She had no obvious facial deformity. Ocular examination revealed a visual acuity of 6/7.5 (20/25) in both eyes, a - 2 . 7 5 sph + 1.75 cyl x 90° in the right eye, and a - 2 . 7 5 sph + 1.75 cyl x 90° in the left eye. Intraocular pressure was 18 mm Hg in each eye. The corneas, irides, and lenses were normal. However, gonioscopy of the left eye showed a peripheral iris strand extending to an area in front of Schwalbe's ring at the 5 o'clock position. Never theless, Schwalbe's ring was in its normal position and of normal thickness. Retinas were unremark able. Karyotype was 46, XX, 2 q - , 9 p + . Case II-3—The proband's 23-year-old maternal uncle was confined to a nursing home because of severe mental retardation. He exhibited the charac teristic gait of the male members of the family, sparse blond hair, low-set ears, beaked nose, and antimongoloid slant of the palpebral fissures (Fig. 6). There was camptodactyly of the fifth digits and warts on the dorsum of each hand as well as a
Uui.
#w-
*LK
JUkMMjUk *«_MLJ!». •t
.ML
JWUUL-M. .*.»*
S*
If:
A*.
Fig. 3 (Cotlier, Reinglass, and Rosenthal). III-l. Giemsa-banding karyotype of the proband demonstrates extra chromatin segment in short arm of chromosome 9 (arrow).
Fig. 4 (Cotlier, Reinglass, and Rosenthal). III-3. Facial features of the sister of the proband.
254
AMERICAN JOURNAL O F OPHTHALMOLOGY
AUGUST, 1977
U ) Fig. 5 (Cotlier, Reinglass, and Rosenthal). III-3. G-banded chromosomes show translocation from long arm of chromosome 2 to short arm of chromosome 9 (arrow).
coccygeal deformity with callous formation. Testi cles were undescended. Chest x-ray films showed scarring of the apical portion of both lungs with pleural thickening. An intravenous pyelogram disclosed grades 2 to 3 pyelactasis and calicectasis; the right ureter was not visible. An audiogram showed a bilateral conductive hearing loss. Ocular examination revealed a 16-degree alternat ing exotropia. Visual acuity could not be determined because of the patient's poor cooperation. Both cor neas had an anteriorly displaced Schwalbe's ring, present both temporally and nasally, and outwardly visible. This was confirmed by gonioscopic exami nation of both anterior chamber angles. Irides were normal. Pupils were round and symmetric bilateral ly; lenses were clear. Ophthalmoscopic examination disclosed some pallor of the optic nerve heads. Karyotype was 46, XY, 9p+.
Case II-4—The proband's third maternal uncle, a retarded 20-year-old, had the same,sparse blond hair, beaked nose, low-set ears, and antimongoloid slant of the palpebral fissures. Further examination revealed a high-arched palate, bridged simian creas es of each palm, a calloused coccygeal malforma tion, and the bent-over shuffling gait. Posture was distinctive (Fig. 7). Clinodactyly was also present. Chest x-ray films showed fibrotic changes of both lung apices. Negative results were obtained from the first and second strengths of the purified protein derivative tests. Audiometry showed neurosensory hearing loss in the left ear. X-ray films revealed chronic sinusitis of the left maxillary sinus. Intrave nous pyelogram showed right calicectasis; the right ureter was not visible. Ocular examination revealed an unsteady fixation of the right eye, and central and steady fixation of the left eye. The right eye showed sclerocornea
■/m
Fig. 6 (Cotlier, Reinglass, and Rosenthal). II-3. Facial features of the uncle of the proband.
VOL. 84, NO. 2
EYE IN P A R T U L TRISOMY 2q SYNDROME
255
superiorly and superficial corneal vessels inferiorly. There was chronic bilateral blepharoconjunctivitfs with crusting of the eyelashes and marked trichiasis (Fig. 8). Constant right exotropia of 24 degrees was present. Nystagmus was elicited in both right and left lateral gaze. Both eyes elevated poorly. Blepharoptosis with poor eyelid closure was present in the right eye. The right anterior chamber was aphakic; the left eye was normal. Applanation tomometry showed intraocular pressures of 55 mm Hg in the Fig. 8 (Cotlier, Reinglass, and Rosenthal). II-4. Note eyebrows meeting in midline, mild antimongoloid slant of palpebral fissures, blepharoconjunctivitis, trichiasis, right exotropia, and blepharoptosis. right eye, and 16 mm Hg in the left eye. There was an inferior coloboma of the right pupil, and the inferiorly displaced right lens (Fig. 9) was cataractous with anteroposterior cortical and nuclear changes. The vitreous showed multiple whitish opacities. Examination of the right fundus revealed an inferior coloboma that included the optic disk, choroid, and retina. The left fundus was normal. According to an ultrasound examination, axial length measurement of the right eye was 30 mm, and on the left, 22 mm. G-banding of the chromosomes revealed 46, XY,9p+. We treated the glaucoma medically. We made many unsuccessful attempts to remove the eyelashes that irritated the cornea. During hospitalization, when further examination revealed poor eyelid clo sure, we performed a mediolateral tarsorrhaphy, and at the same time excised an epidermoid cyst near the left lateral canthus.
Fig. 7 (Cotlier, Reinglass, and Rosenthal). II-3. Posture of the uncle of the proband.
Fig. 9 (Cotlier, Reinglass, and Rosenthal). II-4. Vascularized cornea (inferior ramifications) and dis located cataractous lens in right eye.
256
AMERICAN JOURNAL OF OPHTHALMOLOGY
Case 1-1—The 55-year-old grandfather of the proband had a history of lung carcinoma, resected in 1969. Physical examination was unremarkable. Karyotype was normal. He refused ocular examination. Case 1-2—Ophthalmic and physical examina tions of the proband's 53-year-old grandmother were within normal limits. Karyotype was 46, XX, 2q-,9p+. DISCUSSION
The ocular manifestations in our pedi grees (partial trisomy of the long arm of chromosome 2) have diagnostic impor tance and are a link to ocular anomalies involving facial or skeletal disorders pos sibly caused by undetected chromosomal abnormalities. The uveal colobomas, defects of the anterior chamber angle, congenital glau coma, and dislocated lenses in our patients indicate connective tissue mal formations. Uveal colobomas are occa sionally found in cat's-eye syndrome, 15-17 in the syndrome described by Abbo and Zellweger,18 in the syndrome described by Wolf and associates21 (deletion of the short arm of chromosome4), and in trisomy 13, 18, and 21 syndromes.19 Other syn dromes with associated uveal colobomas include Rubinstein-Taybi,22 facial-medi an cleft,23 first arch,24 orofacial-digital,25 oculosplenic,24 and unclassified, those with oligorphrenia or minimal skeletal dysplasias.26 We did not find the chromo somal abnormalities in the last six catego ries in our pedigree; however, a methodic search, including banding techniques, was not carried out. In two members of our pedigree, Schwalbe's ring of the anterior chamber angle was anteriorly displaced and iridocorneal adhesions were present. The association of an extra metacentric chro mosome with anomalies of the anterior chamber angle (Rieger's syndrome) has been reported.27 However, neither atro phy of the mesodermal leaf of the iris nor abnormalities of the pupil were found among our patients. Although one patient (II-4) had an inferior iris defect, it was
AUGUST, 1977
associated with a coloboma of the retina and choroid. Our proband had enamel hypoplasia of the deciduous teeth; however, no dental anomalies were found among the others. This contrasts with the findings in Rieger's syndrome where such anomalies are prominent. 28 Tabbara, Khouri, and Der Kaloustian27 reported a case of Rieger's syndrome with chromosomal anomalies. Significant clin ical findings were bilateral defects of the anterior chamber angles, microcornea, pseudopolycoria, dyscoria, corectopia, and glaucoma of the right eye. The left eye had a mature lens and incomplete aniridia. Systemic findings revealed an asthenic habitus with decreased facial and body hair, mental retardation, and hypoplastic maxilla with complete anodontia. An extra metacentric chromo some, similar to a G chromosome, and a missing large chromosome in group C 27 were part of the chromosomal anomaly. The mental retardation, facial and skele tal anomalies, and abnormal anterior chamber angles in their patient27 also occurred in the males in our pedigree. Both the proband and his brother (III2) had the distinctive bird-like facies con comitant with micrognathia, beaked nose, and protruding nasomaxillary complex. The maternal uncles (II-1, II-3, II-4) had a similar phenotype. Other syndromes demonstrate these bird-like facies and oc ular abnormalities (Table). Chromosomal anomalies have also been detected in the syndrome described by Wolf and associ ates (a deletion of the short arm of chro mosome 4). 21 By and large, chromosomal studies have not been routinely included in the examination of patients with bird like facies. Banding techniques have been applied even less frequently. The inci dence of balanced chromosomal translocation and other chromosomal anomalies in women with a history of fetal wastage is about one in ten. 35 Family history of
VOL. 84, N O . 2
E Y E IN PARTIAL TRISOMY 2q SYNDROME
SYNDROMES W I T H BIRD-LIKE
Syndrome
Partial trisomy 2 Hallerman-Streiff29"31 Seckel's bird-headed dwarfism32 Treacher-Collins33-34 Wolf and associates21
Mental Retardation
Cleft Palate
Microcephaly
+ -
+
+ +
257
AND OCULAR ANOMALIES
Congenital Heart Disease
Skeletal Anomalies
Hearing Loss
Undescended Testicles
-
+
+
+
+
+
+
+ + +
+
+
+
-
-
-
our pedigree revealed three stillbirths. Chromosomal studies are an important diagnostic tool and should form an inte gral part of the examination of patients with malformation defects involving the eyes and of their phenotypically normal relatives. SUMMARY
Mandibulofacial dysostosis, mental re tardation, skeletal, genital, and ocular malformations occurred in a family with partial trisomy of the long arm of chromo some 2. Translocation of chromatin mate rial from the long arm of chromosome 2 to the short arm of chromsome 9 was bal anced in the female carriers of the pedi gree but was unbalanced among the males. Ocular signs in the males included uveal coloboma, anterior chamber angle anomalies as in Rieger's syndrome, con genital glaucoma with dislocated lens; exotropia, and blepharoconjunctivitis. These findings were related to an inherit ed malformation syndrome. REFERENCES 1. Lewandowski. R. C , Jr., and Yunis, J. J.: New chromosomal syndromes. Am. J. Dis. Child. 129: 515, 1975. 1 Pfeiffer, R. A., Diekman, L., and Buchner, T.: Familiar occurrence of a small metacentric extra chromosome with satellites on both ends. Ann. Genet. 16:124, 1067. 3. Armendares, S., Buentello, L., Cuevas-Sosa, A.,
+
+
and Cantu-Garze, J. M.: Familial extracentric biatellited chromosome. Cytogenetics 8:177, 1969. 4. Borges, W. H., and Wald, N.: A diminutive satellited chromosome in a father and in one of two true hermaphrodite progeny. J. Pediatr. 63:474, 1963. 5. Borgaonkar, D. S., McKusick, V. A., and Farber, P. A.: An inherited small extra chromosome: A mother with 46 X,S t(17,22) (pi, ql) and a son with 47, XY + der (22) mat. J. Med. Genet. 10:379, 1973. 6. Maclntyre, M. N., Walden, D. B., and Henpel, J. M.: Tertiary trisomy in a human kindred contain ing an E/G translocation. Am. J. H u m . Genet. 2 3 : 431, 1971. 7. Weber, F., Muller, H., and Sparkes, R.: The 9 p trisomy syndrome due to inherited translocation. Birth Defects 9:201, 1975. 8. Thompson, H.: Familial chromosomal translo cation with distinctive phenotype d u e to effective trisomy of No. 9p. Birth Defects 9:213, 1975. 9. Wilroy, R. S., Jr., Summitt, R. L., and Martens, P. R.: Partial trisomy for different segments of chromosome 13 in several individuals of the same family. Birth Defects 9:217, 1975. 10. Fawcett, W. A., McCord, W. K., and Francke, U.: Trisomy 14 q - . Birth Defects 9:223, 1975. 11. Schmickel, R., Poznanski, A., and Himebaugh, J.: 16 q trisomy in a family with a balanced 15/16 translocation. Birth Defects 9:229, 1975. 12. Opitz, J. M., and Patau, K.: A partial trisomy 5 p syndrome. Birth Defects 9:191, 1975. 13. Robertson, K. P., Thurmon, T. F., and Tracy, M, C : Acrocephalosyndactyly and partial trisomy 6. Birth Defects 9:267, 1975. 14. Hermann, J., Ruffle, T., Meisner, L. F., Viseskul, C , and Gilbert, E. F.: The partial trisomy 3 q syndrome. Birth Defects 9:340, 1975. 15. Schachenmann, G., Sehmid, W., Fraccaro, M., Mannini, A., Tiepolo, L., Perona, G. P., and Sartori, E.: Chromosomes in coloboma and anal atresia. Lancet 2:290, 1965. 16. Weber, F . M., Dooley, R. R., and Sparkes, R. S.: Anal atresia, eye anomalies, and an additional small abnormal acrocentric chromosome 47, XX, mar + . J. Pediatr. 76:594, 1970.
258
AMERICAN JOURNAL O F OPHTHALMOLOGY
17. Gerland, P. S., Davis, D., Say, B. M., and Wilkins, J. L.: A novel chromosomal basis for imperforate anus (the "cat-eye" syndrome). Pediatr. Res. 2:297, 1968. 18. Abbo, G., and Zellweger, H.: The syndrome of the metacentric microchromosome. Helv. Paediatr. Acta 25:83, 1970. 19. Apple, D. J.: Chromosome-induced ocular disease. In Goldberg, M. F. (ed.); Genetic and Metabolic Eye Disease. Boston, Little, Brown, 1974, pp. 527-549. 20. Rosenthal, I. M., Deligere, N., Thompson, F., Pruzansky, S., and Reihglass, H.: Trisomy of the distal portion of the long arm of chromosome 2: A new familial syndrome associated with mental retar dation and a characteristic facies. Am. J. Hum. Genet. 26:73, 1974. 21. Wolf, U., Prosch, R., Baitsh, H., and Reinwein, H.: Deletion on short arms of a B-chromosome without "cri du chat" syndrome. Lancet 1:769, 1965. 22. Roy, F. H., Summitt, R. L., Hiatt, R. L., and Hughes, J. G.: Ocular manifestations of the Rubinstein-Taybi syndrome. Arch. Ophthalmol. 79:272, 1968. 23. Frangois, J., Eggermont, E., Evens, L., Loggbe, N., and DeBock, F.: Agenesis of the corpus callosum in the median facial cleft syndrome and associated ocular malformations. Am. J. Ophthal mol. 76:241, 1973. 24. James, P. M. L., Karseras, A. G.,.and Wybar, K. C,: Systemic associations of uveal coloboma. Br. J. Ophthalmol. 58:917, 1974. 25. Gorlin, R. J., and Psaume, J.: Orodigitofacial
AUGUST, 1977
dysostosis: A new syndrome. J. Pediatr. 61:520, 1962. 26. Warburg, M.: The heterogeneity of microphthalmia in the mentally retarded. Birth Defects 7: 136, 1971. 27. Tabbara, K. F., Khouri, F. P., and Der Kaloustian, V. M.: Rieger's syndrome with chromosomal anomaly. Can. J. Ophthalmol. 8:488, 1973. 28. Alkemade, P. P. H.: Dysgenesis Mesodermalis of the Iris and the Cornea. A Study of Rieger's Syndrome and Peter's Anomaly. The Netherlands, Royal van Gorcum, 1969, pp. 87-88. 29. Hallerman, W.: Vogelgesicht und Cataracta congenita. Klin. Monatsbl. Augenheilkd. 113:315, 1948. 30. Streiff, E. B.: Dysmorphie mandibulo-faciale (tfete d'oiseau) et alterations oculaires. Ophthalmologica 120:79, 1950. 31. Frangois, J.: A new syndrome: Dyscephalia with bird-face and dental anomalies, nanism, hypotrichosis, cutaneous atrophy, micrpphthalmia, and congenital cataract. Arch. Ophthalmol. 60:842, 1958. 32. Seckel, H. P. G.: Bird-Headed Dwarfs. Springfield, Charles C Thomas, 1960, pp. 35-36. 33. Treacher-Collins, E.: Case with symmetrical congenital notches in the outer part of each lower lid and defective development of the malar bones. Trans. Ophthalmol. Soc. U.K. 20:190, 1900. 34. Kirkham, T. H.: Mandibulofacial dysostosis with ectopia lentis. Am. J. Ophthalmol. 70:947, 1970. 35. Hirschhorn, K.: Cytogenetics of fetal wastage. N. Engl. J. Med. 293:844, 1975.
Malformation syndromes include skel etal, connective tissue, and neurological morphogenetic abnormalities, many of which manifest typical facies and ocular involvement. Chromosomal defects have been found in children or young adults with malformation syndromes and in their phenotypically normal parents. 1-14 Strabismus or other external ocular signs, a part of many characteristic facies, have been found in the inherited chromosomal defects of 9p+ trisomy with translocation to chromosome 22 or chromosome 1, tri somy 14q-, trisomy 16q, and partial trisomy 6. Ocular anomalies have also been associated with small extra chromo somes in the cat's-eye syndrome, 15-17 in the syndrome described by Abbo and Zelweger,18 and in the trisomjes 13, 18, and 21. 1 9 In the latter, the chromosomal defects are not usually inherited. Two of us (I.R., H.R.)20 described a new inherited syndrome of mandibulofacial dysotosis with skeletal, genital, and ocular manifestations. These anomalies were associated with trisomy of the distal portion of the long arm of chromosome 2, resulting from translocation to the short arm of chromosome 9. Here we describe the ocular findings in the affected males of that pedigree. We also detected anoma lies of the anterior chamber angles in one carrier female. From the Departments of Ophthalmology (Drs. Cotlier and Reinglass) and Pediatrics (Dr. Rosenthai), University of Illinois Medical Center, Chica go, Illinois. Reprint requests to Edward Cotlier, M.D., Depart ment of Ophthalmology, State University of New York at Buffalo, Buffalo General Hospital, 100 High St., Buffalo, NY 14203.
METHODS
Karyotypes were prepared with Giemsa banding from peripheral lymphocytes and cephalometric roentgenograms were analyzed. Ophthalmic examination in cluded testing of visual acuity and extraocular motility, gonioscopy, ophthalmoscopy with depression of the periphery, slit-lamp examination, and Goldmann three-mirror lens examination. In selected members of the pedigree (Fig. 1), the anterior chamber angle was photo graphed. CASE REPORTS Case III-I—The proband was a mentally retarded, 5-year-old white boy with low-set ears, a beaked nose, and sparse blond hair (Fig. 2). Examination revealed undescended testes, bilateral camptodactyly of the fifth digits, and an eczematous rash with lichenified lesions on the extensor surfaces of the extremities and on the trunk. Two procedures had been carried out for closure of a congenital cleft of both hard and soft palates, but a small residual stoma remained. Karyotypes prepared from periph eral lymphocytes with G-banding revealed a pattern of 46, XY, 9p+, representing unbalanced transloca tion to the short arm of chromosome 9 (Fig. 3).
3
TL-J* I
[2
3
4
ut>
HI /
I
2
3
Fig. 1 (Cotlier, Reinglass, and Rosenthal). Family pedigree of partial trisomy 2 syndrome of craniofacial, skeletal, gonadal, and ocular abnormalities. Arrow denotes proband.
251
252
AMERICAN JOURNAL OF OPHTHALMOLOGY
Fig. 2 (Cotlier, Reinglass, and Rosenthal). I I I - l . Facial features of the proband show typical bird-like facies.
cytogenetic studies of other family members indi cated that the translocated segment was derived from the long arm of chromosome 2. Ocular examination revealed an antimongoloid slant to the palpebral fissures. Central and steady fixation was present bilaterally. Left exotropia of 16 degrees was found in the primary position of gaze and when looking up and down. The patient had chronic blepharitis of the left eye. Examination showed an externally visible, anterior displacement of Schwalbe's ring in the right eye. Gonioscopy could not be performed because of the patient's lack of cooperation. Refraction showed - 1 . 0 0 sph + 1.00 cyl x 180° in the right eye, and - 3 . 5 0 sph + 1.50 cyl x 180° in the left eye. The maculae were granular with poor foveal reflexes. The disks, irides, lenses, and pupils appeared normal in both eyes. Case IH-2—A 3-year-old younger brother of the proband died from an overwhelming infection. At autopsy, multiple abcesses were found in the brain and kidneys. He also had a congenital cleft palate, sparse blond hair, mental retardation, low-set ears, beaked nose, antimongoloid slant to the eyes, and camptodactyly of the fifth digits of each hand. Our review of a karyotype (not banded) prepared else
AUGUST, 1977
where revealed the abnormal chromosome 9, as found in the proband. A detailed ophthalmologic examination was never performed. Case III-3—The proband's 7-year-old sister had normal facial and skeletal features (Fig. 4). Visual acuity was 6/7.5 (20/25) with a +0.75 sph in each eye. The remaining examination, including gonio scopy, was within normal limits. Karyotype was 46, XX, 2 q - , 9 p + . This was an apparently balanced translocation of the distal segment of the long arm of chromosome 2 to the short arm of chromosome 9. G-banding revealed the exact location of the translo cation (Fig. 5). Case II-1—The proband's 27-year-old maternal uncle had a heart murmur, a grade 2/6 systolic ejection murmur, and undescended testicles. He had a history of seizures for which he was taking medi cation. He also had sparse blond hair, low-set ears, and a beaked nose. He walked with a distinctive, forward-leaning gait. Camptodactyly of the fifth digit was present bilaterally. Ocular examination revealed an antimongoloid slant to the palpebral fissures. Although visual acu ity could not be obtained, the patient had a central and steady fixation of the right eye and a central but wandering fixation of the left eye. Examination for ocular motility showed no heterotropia and a full range of motion of extraocular muscles. There was chronic blepharitis with crusting of both upper and lower eyelids of each eye. The conjunctivae were clear, but the corneas showed limbal scarring from previous staphylococcal ulcers. Slit-lamp examina tion of the corneas revealed a displaced and hypertrophied Schwalbe's ring bilaterally and anteriorly. We saw no increased iris processes. Both retinas had cobblestone degeneration of the inferior temporal quadrants. Chromosomal study disclosed a 46, XY, 9p + pattern. By G-banding, the extra chromatin material on the short arm of chromosome 9 was identified as a portion of the long arm of chromosome 2. Case II-2—The proband's 25-year-old mother had unremarkable skeletal and facial features except for a slightly beaked nose. Posture and gait were nor mal. She had no obvious facial deformity. Ocular examination revealed a visual acuity of 6/7.5 (20/25) in both eyes, a - 2 . 7 5 sph + 1.75 cyl x 90° in the right eye, and a - 2 . 7 5 sph + 1.75 cyl x 90° in the left eye. Intraocular pressure was 18 mm Hg in each eye. The corneas, irides, and lenses were normal. However, gonioscopy of the left eye showed a peripheral iris strand extending to an area in front of Schwalbe's ring at the 5 o'clock position. Never theless, Schwalbe's ring was in its normal position and of normal thickness. Retinas were unremark able. Karyotype was 46, XX, 2 q - , 9 p + . Case II-3—The proband's 23-year-old maternal uncle was confined to a nursing home because of severe mental retardation. He exhibited the charac teristic gait of the male members of the family, sparse blond hair, low-set ears, beaked nose, and antimongoloid slant of the palpebral fissures (Fig. 6). There was camptodactyly of the fifth digits and warts on the dorsum of each hand as well as a
Uui.
#w-
*LK
JUkMMjUk *«_MLJ!». •t
.ML
JWUUL-M. .*.»*
S*
If:
A*.
Fig. 3 (Cotlier, Reinglass, and Rosenthal). III-l. Giemsa-banding karyotype of the proband demonstrates extra chromatin segment in short arm of chromosome 9 (arrow).
Fig. 4 (Cotlier, Reinglass, and Rosenthal). III-3. Facial features of the sister of the proband.
254
AMERICAN JOURNAL O F OPHTHALMOLOGY
AUGUST, 1977
U ) Fig. 5 (Cotlier, Reinglass, and Rosenthal). III-3. G-banded chromosomes show translocation from long arm of chromosome 2 to short arm of chromosome 9 (arrow).
coccygeal deformity with callous formation. Testi cles were undescended. Chest x-ray films showed scarring of the apical portion of both lungs with pleural thickening. An intravenous pyelogram disclosed grades 2 to 3 pyelactasis and calicectasis; the right ureter was not visible. An audiogram showed a bilateral conductive hearing loss. Ocular examination revealed a 16-degree alternat ing exotropia. Visual acuity could not be determined because of the patient's poor cooperation. Both cor neas had an anteriorly displaced Schwalbe's ring, present both temporally and nasally, and outwardly visible. This was confirmed by gonioscopic exami nation of both anterior chamber angles. Irides were normal. Pupils were round and symmetric bilateral ly; lenses were clear. Ophthalmoscopic examination disclosed some pallor of the optic nerve heads. Karyotype was 46, XY, 9p+.
Case II-4—The proband's third maternal uncle, a retarded 20-year-old, had the same,sparse blond hair, beaked nose, low-set ears, and antimongoloid slant of the palpebral fissures. Further examination revealed a high-arched palate, bridged simian creas es of each palm, a calloused coccygeal malforma tion, and the bent-over shuffling gait. Posture was distinctive (Fig. 7). Clinodactyly was also present. Chest x-ray films showed fibrotic changes of both lung apices. Negative results were obtained from the first and second strengths of the purified protein derivative tests. Audiometry showed neurosensory hearing loss in the left ear. X-ray films revealed chronic sinusitis of the left maxillary sinus. Intrave nous pyelogram showed right calicectasis; the right ureter was not visible. Ocular examination revealed an unsteady fixation of the right eye, and central and steady fixation of the left eye. The right eye showed sclerocornea
■/m
Fig. 6 (Cotlier, Reinglass, and Rosenthal). II-3. Facial features of the uncle of the proband.
VOL. 84, NO. 2
EYE IN P A R T U L TRISOMY 2q SYNDROME
255
superiorly and superficial corneal vessels inferiorly. There was chronic bilateral blepharoconjunctivitfs with crusting of the eyelashes and marked trichiasis (Fig. 8). Constant right exotropia of 24 degrees was present. Nystagmus was elicited in both right and left lateral gaze. Both eyes elevated poorly. Blepharoptosis with poor eyelid closure was present in the right eye. The right anterior chamber was aphakic; the left eye was normal. Applanation tomometry showed intraocular pressures of 55 mm Hg in the Fig. 8 (Cotlier, Reinglass, and Rosenthal). II-4. Note eyebrows meeting in midline, mild antimongoloid slant of palpebral fissures, blepharoconjunctivitis, trichiasis, right exotropia, and blepharoptosis. right eye, and 16 mm Hg in the left eye. There was an inferior coloboma of the right pupil, and the inferiorly displaced right lens (Fig. 9) was cataractous with anteroposterior cortical and nuclear changes. The vitreous showed multiple whitish opacities. Examination of the right fundus revealed an inferior coloboma that included the optic disk, choroid, and retina. The left fundus was normal. According to an ultrasound examination, axial length measurement of the right eye was 30 mm, and on the left, 22 mm. G-banding of the chromosomes revealed 46, XY,9p+. We treated the glaucoma medically. We made many unsuccessful attempts to remove the eyelashes that irritated the cornea. During hospitalization, when further examination revealed poor eyelid clo sure, we performed a mediolateral tarsorrhaphy, and at the same time excised an epidermoid cyst near the left lateral canthus.
Fig. 7 (Cotlier, Reinglass, and Rosenthal). II-3. Posture of the uncle of the proband.
Fig. 9 (Cotlier, Reinglass, and Rosenthal). II-4. Vascularized cornea (inferior ramifications) and dis located cataractous lens in right eye.
256
AMERICAN JOURNAL OF OPHTHALMOLOGY
Case 1-1—The 55-year-old grandfather of the proband had a history of lung carcinoma, resected in 1969. Physical examination was unremarkable. Karyotype was normal. He refused ocular examination. Case 1-2—Ophthalmic and physical examina tions of the proband's 53-year-old grandmother were within normal limits. Karyotype was 46, XX, 2q-,9p+. DISCUSSION
The ocular manifestations in our pedi grees (partial trisomy of the long arm of chromosome 2) have diagnostic impor tance and are a link to ocular anomalies involving facial or skeletal disorders pos sibly caused by undetected chromosomal abnormalities. The uveal colobomas, defects of the anterior chamber angle, congenital glau coma, and dislocated lenses in our patients indicate connective tissue mal formations. Uveal colobomas are occa sionally found in cat's-eye syndrome, 15-17 in the syndrome described by Abbo and Zellweger,18 in the syndrome described by Wolf and associates21 (deletion of the short arm of chromosome4), and in trisomy 13, 18, and 21 syndromes.19 Other syn dromes with associated uveal colobomas include Rubinstein-Taybi,22 facial-medi an cleft,23 first arch,24 orofacial-digital,25 oculosplenic,24 and unclassified, those with oligorphrenia or minimal skeletal dysplasias.26 We did not find the chromo somal abnormalities in the last six catego ries in our pedigree; however, a methodic search, including banding techniques, was not carried out. In two members of our pedigree, Schwalbe's ring of the anterior chamber angle was anteriorly displaced and iridocorneal adhesions were present. The association of an extra metacentric chro mosome with anomalies of the anterior chamber angle (Rieger's syndrome) has been reported.27 However, neither atro phy of the mesodermal leaf of the iris nor abnormalities of the pupil were found among our patients. Although one patient (II-4) had an inferior iris defect, it was
AUGUST, 1977
associated with a coloboma of the retina and choroid. Our proband had enamel hypoplasia of the deciduous teeth; however, no dental anomalies were found among the others. This contrasts with the findings in Rieger's syndrome where such anomalies are prominent. 28 Tabbara, Khouri, and Der Kaloustian27 reported a case of Rieger's syndrome with chromosomal anomalies. Significant clin ical findings were bilateral defects of the anterior chamber angles, microcornea, pseudopolycoria, dyscoria, corectopia, and glaucoma of the right eye. The left eye had a mature lens and incomplete aniridia. Systemic findings revealed an asthenic habitus with decreased facial and body hair, mental retardation, and hypoplastic maxilla with complete anodontia. An extra metacentric chromo some, similar to a G chromosome, and a missing large chromosome in group C 27 were part of the chromosomal anomaly. The mental retardation, facial and skele tal anomalies, and abnormal anterior chamber angles in their patient27 also occurred in the males in our pedigree. Both the proband and his brother (III2) had the distinctive bird-like facies con comitant with micrognathia, beaked nose, and protruding nasomaxillary complex. The maternal uncles (II-1, II-3, II-4) had a similar phenotype. Other syndromes demonstrate these bird-like facies and oc ular abnormalities (Table). Chromosomal anomalies have also been detected in the syndrome described by Wolf and associ ates (a deletion of the short arm of chro mosome 4). 21 By and large, chromosomal studies have not been routinely included in the examination of patients with bird like facies. Banding techniques have been applied even less frequently. The inci dence of balanced chromosomal translocation and other chromosomal anomalies in women with a history of fetal wastage is about one in ten. 35 Family history of
VOL. 84, N O . 2
E Y E IN PARTIAL TRISOMY 2q SYNDROME
SYNDROMES W I T H BIRD-LIKE
Syndrome
Partial trisomy 2 Hallerman-Streiff29"31 Seckel's bird-headed dwarfism32 Treacher-Collins33-34 Wolf and associates21
Mental Retardation
Cleft Palate
Microcephaly
+ -
+
+ +
257
AND OCULAR ANOMALIES
Congenital Heart Disease
Skeletal Anomalies
Hearing Loss
Undescended Testicles
-
+
+
+
+
+
+
+ + +
+
+
+
-
-
-
our pedigree revealed three stillbirths. Chromosomal studies are an important diagnostic tool and should form an inte gral part of the examination of patients with malformation defects involving the eyes and of their phenotypically normal relatives. SUMMARY
Mandibulofacial dysostosis, mental re tardation, skeletal, genital, and ocular malformations occurred in a family with partial trisomy of the long arm of chromo some 2. Translocation of chromatin mate rial from the long arm of chromosome 2 to the short arm of chromsome 9 was bal anced in the female carriers of the pedi gree but was unbalanced among the males. Ocular signs in the males included uveal coloboma, anterior chamber angle anomalies as in Rieger's syndrome, con genital glaucoma with dislocated lens; exotropia, and blepharoconjunctivitis. These findings were related to an inherit ed malformation syndrome. REFERENCES 1. Lewandowski. R. C , Jr., and Yunis, J. J.: New chromosomal syndromes. Am. J. Dis. Child. 129: 515, 1975. 1 Pfeiffer, R. A., Diekman, L., and Buchner, T.: Familiar occurrence of a small metacentric extra chromosome with satellites on both ends. Ann. Genet. 16:124, 1067. 3. Armendares, S., Buentello, L., Cuevas-Sosa, A.,
+
+
and Cantu-Garze, J. M.: Familial extracentric biatellited chromosome. Cytogenetics 8:177, 1969. 4. Borges, W. H., and Wald, N.: A diminutive satellited chromosome in a father and in one of two true hermaphrodite progeny. J. Pediatr. 63:474, 1963. 5. Borgaonkar, D. S., McKusick, V. A., and Farber, P. A.: An inherited small extra chromosome: A mother with 46 X,S t(17,22) (pi, ql) and a son with 47, XY + der (22) mat. J. Med. Genet. 10:379, 1973. 6. Maclntyre, M. N., Walden, D. B., and Henpel, J. M.: Tertiary trisomy in a human kindred contain ing an E/G translocation. Am. J. H u m . Genet. 2 3 : 431, 1971. 7. Weber, F., Muller, H., and Sparkes, R.: The 9 p trisomy syndrome due to inherited translocation. Birth Defects 9:201, 1975. 8. Thompson, H.: Familial chromosomal translo cation with distinctive phenotype d u e to effective trisomy of No. 9p. Birth Defects 9:213, 1975. 9. Wilroy, R. S., Jr., Summitt, R. L., and Martens, P. R.: Partial trisomy for different segments of chromosome 13 in several individuals of the same family. Birth Defects 9:217, 1975. 10. Fawcett, W. A., McCord, W. K., and Francke, U.: Trisomy 14 q - . Birth Defects 9:223, 1975. 11. Schmickel, R., Poznanski, A., and Himebaugh, J.: 16 q trisomy in a family with a balanced 15/16 translocation. Birth Defects 9:229, 1975. 12. Opitz, J. M., and Patau, K.: A partial trisomy 5 p syndrome. Birth Defects 9:191, 1975. 13. Robertson, K. P., Thurmon, T. F., and Tracy, M, C : Acrocephalosyndactyly and partial trisomy 6. Birth Defects 9:267, 1975. 14. Hermann, J., Ruffle, T., Meisner, L. F., Viseskul, C , and Gilbert, E. F.: The partial trisomy 3 q syndrome. Birth Defects 9:340, 1975. 15. Schachenmann, G., Sehmid, W., Fraccaro, M., Mannini, A., Tiepolo, L., Perona, G. P., and Sartori, E.: Chromosomes in coloboma and anal atresia. Lancet 2:290, 1965. 16. Weber, F . M., Dooley, R. R., and Sparkes, R. S.: Anal atresia, eye anomalies, and an additional small abnormal acrocentric chromosome 47, XX, mar + . J. Pediatr. 76:594, 1970.
258
AMERICAN JOURNAL O F OPHTHALMOLOGY
17. Gerland, P. S., Davis, D., Say, B. M., and Wilkins, J. L.: A novel chromosomal basis for imperforate anus (the "cat-eye" syndrome). Pediatr. Res. 2:297, 1968. 18. Abbo, G., and Zellweger, H.: The syndrome of the metacentric microchromosome. Helv. Paediatr. Acta 25:83, 1970. 19. Apple, D. J.: Chromosome-induced ocular disease. In Goldberg, M. F. (ed.); Genetic and Metabolic Eye Disease. Boston, Little, Brown, 1974, pp. 527-549. 20. Rosenthal, I. M., Deligere, N., Thompson, F., Pruzansky, S., and Reihglass, H.: Trisomy of the distal portion of the long arm of chromosome 2: A new familial syndrome associated with mental retar dation and a characteristic facies. Am. J. Hum. Genet. 26:73, 1974. 21. Wolf, U., Prosch, R., Baitsh, H., and Reinwein, H.: Deletion on short arms of a B-chromosome without "cri du chat" syndrome. Lancet 1:769, 1965. 22. Roy, F. H., Summitt, R. L., Hiatt, R. L., and Hughes, J. G.: Ocular manifestations of the Rubinstein-Taybi syndrome. Arch. Ophthalmol. 79:272, 1968. 23. Frangois, J., Eggermont, E., Evens, L., Loggbe, N., and DeBock, F.: Agenesis of the corpus callosum in the median facial cleft syndrome and associated ocular malformations. Am. J. Ophthal mol. 76:241, 1973. 24. James, P. M. L., Karseras, A. G.,.and Wybar, K. C,: Systemic associations of uveal coloboma. Br. J. Ophthalmol. 58:917, 1974. 25. Gorlin, R. J., and Psaume, J.: Orodigitofacial
AUGUST, 1977
dysostosis: A new syndrome. J. Pediatr. 61:520, 1962. 26. Warburg, M.: The heterogeneity of microphthalmia in the mentally retarded. Birth Defects 7: 136, 1971. 27. Tabbara, K. F., Khouri, F. P., and Der Kaloustian, V. M.: Rieger's syndrome with chromosomal anomaly. Can. J. Ophthalmol. 8:488, 1973. 28. Alkemade, P. P. H.: Dysgenesis Mesodermalis of the Iris and the Cornea. A Study of Rieger's Syndrome and Peter's Anomaly. The Netherlands, Royal van Gorcum, 1969, pp. 87-88. 29. Hallerman, W.: Vogelgesicht und Cataracta congenita. Klin. Monatsbl. Augenheilkd. 113:315, 1948. 30. Streiff, E. B.: Dysmorphie mandibulo-faciale (tfete d'oiseau) et alterations oculaires. Ophthalmologica 120:79, 1950. 31. Frangois, J.: A new syndrome: Dyscephalia with bird-face and dental anomalies, nanism, hypotrichosis, cutaneous atrophy, micrpphthalmia, and congenital cataract. Arch. Ophthalmol. 60:842, 1958. 32. Seckel, H. P. G.: Bird-Headed Dwarfs. Springfield, Charles C Thomas, 1960, pp. 35-36. 33. Treacher-Collins, E.: Case with symmetrical congenital notches in the outer part of each lower lid and defective development of the malar bones. Trans. Ophthalmol. Soc. U.K. 20:190, 1900. 34. Kirkham, T. H.: Mandibulofacial dysostosis with ectopia lentis. Am. J. Ophthalmol. 70:947, 1970. 35. Hirschhorn, K.: Cytogenetics of fetal wastage. N. Engl. J. Med. 293:844, 1975.