- Email: [email protected]
Anophthalmia and microphthalmia in the Alberta Congenital Anomalies Surveillance System
Anophthalmia and microphthalmia in the Alberta Congenital Anomalies Surveillance System R. Brian Lowry,*† MD, DSc, FRCPC; Ruth Kohut,‡§ MSc; Barbara Sibbald,*† MSc; Jocelyn Rouleau‡ ABSTRACT • RÉSUMÉ Background: A higher than expected rate of anophthalmia/microphthalmia (A/M) for 1999 was noted in both the Alberta Congenital Anomalies Surveillance System (ACASS) and the Canadian Congenital Anomalies Surveillance System (CCASS). Since this increase was at variance with the previous 19 years, we performed a review to determine whether the increase was true and, if so, the possible explanation. Methods: We reviewed the records of the cases of A/M in the ACASS together with the accompanying attachments (e.g., consultant, autopsy and chromosome reports) for 1991–2001. In addition, we contacted all 91 registered ophthalmologists in Alberta. Letters were also written to the Edmonton and Calgary offices of the Canadian National Institute for the Blind (CNIB). Results: Sixty cases of A/M were ascertained over the study period. Of the 88 active ophthalmologists in the province, 21 (24%) replied, but no new cases were ascertained from this source. No replies were received from the CNIB.We constructed five categories of clinical phenotypes for the 60 cases: 20 had a chromosomal etiology, 13 had a recognized syndrome or association, 16 had extraocular malformations, 5 had other eye anomalies, and 6 had A/M only. Pregnancy terminations were not included.The higher rate in 1999 was mainly due to cases with a chromosomal etiology or a recognized syndrome or association. There was no indication that a teratogen was causing a cluster of A/M cases, as our annual rates were comparable to those for other jurisdictions not only in Canada but also in other countries. Interpretation: Our review confirmed that the rate of A/M in Alberta in 1999 was high but that the increase was mainly due to five cases of trisomy 13 together with one case associated with a syndrome (Meckel–Gruber). Our findings provide reassurance that there was no environmental cause of clustering of anophthalmia or microphthalmia.
From *the Alberta Congenital Anomalies Surveillance System, Health Surveillance, Alberta Health and Wellness, Calgary, Alta., †the Department of Medical Genetics, Alberta Children’s Hospital/University of Calgary, Calgary, Alta., and ‡the Maternal and Infant Health Section, Health Surveillance and Epidemiology Division, Health Canada
Accepted for publication Aug. 11, 2004 Correspondence to: Dr. R. Brian Lowry, Department of Medical Genetics, Alberta Children’s Hospital, 1820 Richmond Rd. SW, Calgary AB T2T 5C7; fax (403) 228-0796; Brian.Lowry@calgary healthregion.ca
§Currently with Healthy Public Policy, Health Promotion/Disease Prevention, Calgary Health Region, Calgary, Alta.
This article has been peer-reviewed.
Originally received Jan. 23, 2004
Can J Ophthalmol 2005;40:38–44
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Anophthalmia/microphthalmia—Lowry et al
Anophthalmia/microphthalmia—Lowry et al
This review demonstrates the importance of ongoing population-based surveillance in providing baseline birth prevalence rates for evaluating trends and clusters. x Contexte : Un taux plus haut que prévu d’anophtalmie/microphtalmie (A/M) a été relevé en 1999 par l’Alberta Congenital Anomalies Surveillance System (ACASS) et le Réseau canadien de surveillance des anomalies congénitales (RCSAC). Comme cela ne correspondait pas aux résultats des 19 années précédentes, nous avons revu la situation pour voir si la hausse était réelle et, le cas échéant, en déceler les explications possibles. Méthodes : Nous avons examiné les dossiers des cas d’A/M relevés par l’ACASS de 1991 à 2001, de même que la documentation afférente à chacun (consultant, autopsie, analyse des chromosomes). En outre, nous avons communiqué avec les 91 ophtalmologistes de l’Alberta. Nous avons aussi écrit aux bureaux d’Edmonton et de Calgary de l’Institut national canadien pour les aveugles (INCA). Résultats : Soixante cas d’A/M ont été établis pendant la période étudiée. Des 88 ophtalmologistes actifs de la province, 21 (24 %) ont répondu, mais cette source n’a confirmé aucun nouveau cas. L’INCA n’a pas répondu. Nous avons constitué cinq catégories de phénotypes cliniques pour les 60 cas : 20 avaient une étiologie chromosomique, 13 avaient un syndrome ou une association reconnus, 16 avaient des malformations extra-oculaires, 5 avaient d’autres anomalies oculaires et 6 avaient une A/M seulement. Les interruptions de grossesse n’ont pas été incluses. Le taux plus élevé de 1999 était surtout attribuable à des cas d’étiologie chromosomique ou de syndrome ou association reconnus. Rien n’indiquait qu’un facteur tératogène avait causé un ensemble de cas d’A/M, car nos taux annuels étaient semblables à ceux des autres juridictions non seulement au Canada mais aussi dans d’autres pays. Interprétation : Notre revue a confirmé que le taux d’A/M de 1999 en Alberta était élevé, mais que la hausse était surtout attribuable à cinq cas de trisomie 13 avec un cas associé à un syndrome, celui de Meckel–Gruber. Nos constatations nous ont rassurés sur l’absence de causes environnementales pour un groupement de cas d’anophtalmie ou de microphtalmie. La revue démontre l’importance d’une surveillance démographique constante qui fournira les taux de base de prévalence à la naissance afin d’évaluer les tendances et les groupements.
I
n preparing statistics for congenital anomalies, we found a higher than expected rate of anophthalmia/ microphthalmia (A/M) for 1999 in the Alberta Congenital Anomalies Surveillance System (ACASS) and in the Canadian Congenital Anomalies Surveillance System (CCASS), 2.4 and 1.87 per 10 000 total births respectively. The CCASS, the national surveillance registry, is a passive system that obtains data from the Discharge Abstract Database of the Canadian Institute for Health Information. The ACASS is a semiactive provincial surveillance system with the ability to seek out further information from medical records and consultant and laboratory reports.
Most provincial rates for A/M for 1991–99 were approximately 1/10 000 total births, with four exceptions: Quebec, 1.6, Nova Scotia, 1.8, Newfoundland, 2.5, and Saskatchewan, 2.5 (Table 1). The rate for Canada for the same period was 1.2, and for Alberta, 1.0 in the CCASS and 1.3 in the ACASS. A review of the rates of A/M in the ACASS for the 19-year period 1980–98 showed that the rate per 10 000 varied from 0.3 to 2.1, the 19-year aggregate rate being 1.4. The rate of 2.4 in 1999 was therefore completely at variance with the previous 19 years (ratio of observed to expected: 1.714, p = 0.02). We performed a review to determine whether the increase was true and, if so, the possible explanation.
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Table 1—Rates of anophthalmia/microphthalmia (A/M) in Canada for 1991–99 by province/territory
Province/territory
No. of cases
Rate per 10 000 total births (and 95% CI)
Yukon Territory Northwest Territories British Columbia Alberta* Saskatchewan Manitoba Ontario Quebec New Brunswick Nova Scotia Prince Edward Island Newfoundland
0 1 46 36 30 17 123 126 10 7 0 13
0 0.9 1.1 1.0 2.5 1.2 0.9 1.6 1.3 1.8 0 2.5
Canada
409
1.2 (1.1–1.4)
(0.01–5.2) (0.8–1.5) (0.7–1.4) (1.7–3.6) (0.7–1.9) (0.8–1.1) (1.3–1.9) (0.6–2.3) (0.7–3.6) (1.3–4.2)
Source: Canadian Congenital Anomalies Surveillance System (CCASS), Health Canada. Note: CI = confidence interval. *The rates reported by the CCASS and the Alberta Congenital Anomalies Surveillance System (ACASS) can vary. The ACASS contains 46 cases for 1991–99, whereas the CCASS contains 36 cases.
METHODS We reviewed the Alberta cases of A/M for the period 1991–2001 by retrieving the actual Congenital Anomaly Reporting Form plus any accompanying attachments (e.g., ophthalmology or other consultant reports, autopsy report, chromosome reports). In addition, we wrote, emailed or faxed letters to all 91 registered ophthalmologists in Alberta, asking whether they had any unreported cases of A/M. We also wrote to the Edmonton and Calgary branches of the Canadian National Institute for the Blind (CNIB). Unfortunately, it was not possible to review the cases from the CCASS. In reviewing cases of A/M and attempting to assign etiology it is often impossible to be precise as to the cause because of the heterogeneity of the disorders. At times, anophthalmia and microphthalmia are difficult to distinguish without histologic or ultrasound examination. The definition used by the International Clearinghouse for Birth Defects Monitoring Systems states: “Anophthalmos/ microphthalmos: apparently absent or small eyes. Some normal adnexal elements and eyelids are usually present. In microphthalmia, the corneal diameter is usually less than 10 mm. and the antero-posterior diameter of the globe is less than 20 mm.”1 In actual practice we accept
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a clinician’s description of these features without measurement, but we recognize the problems of case definition and lack of standardization between studies. Anophthalmia and microphthalmia may have the same etiology, as an affected person may have anophthalmia in one eye and microphthalmia in the other. Optic fissure closure defects (i.e., coloboma) are also part of the A/M phenotype. In calculating the ratio of observed to expected cases we used the aggregate rate for 1980–98 as the baseline. Since this was deemed to be a quality-control survey and part of the provincial department of health mandate for surveillance, permission from the Conjoint Ethics Board of the University of Calgary was not required.
RESULTS Sixty cases of A/M were ascertained over the period 1991–2001. Of the 88 active ophthalmologists in the province, 21 (24%) replied. No new cases were ascertained from this source. No replies were received from the CNIB. We constructed five categories of clinical phenotypes for the 60 cases: 20 (33%) had a chromosomal etiology (trisomy 13 in 16 cases, and, in 1 case each, trisomy 18, triploidy, 6q minus and 3 deletion/inversion) (Table 2). In 13 cases there was a recognized syndrome or association (Aicardi, amniotic band, CHARGE, Gorlin–Cohen [frontometaphyseal dysplasia], complex I deficiency, Hallermann–Streiff, ichthyosis, Lenz, Meckel– Gruber, Nager acrofacial dysostosis, sebaceous nevus, VATER or Walker–Warburg). Sixteen cases (27%) were associated with extraocular malformations, including holoprosencephaly in four (normal chromosomes were present in three of the four). There were six cases of A/M plus coloboma and five cases with other eye anomalies (cataract and persistent hyperplastic primary vitreous in two, isolated cataract in two, and aniridia and corneal opacity in one). The 11 cases with ocular defects corresponded to a rate of 0.2/10 000 total births, with the other categories (chromosomal, syndromal and multiple congenital anomaly) having a rate of 1.2/10 000. The annual rates are shown in Table 2. Over this period the rate for Alberta was 1.4/10 000. There were no appreciable differences in birth weight or gestational age between the cases with and without normal chromosomes. However, mean maternal age was lower for the cases with an abnormal karyotype than for those with a normal karyotype (25.6 vs. 30.4 years). The increased rate of A/M in 1999 was statistically significant (ratio of observed to expected: 1.71, p = 0.02).
INTERPRETATION There is marked variation in reported rates of A/M
Anophthalmia/microphthalmia—Lowry et al
Table 2—A/M in Alberta, 1991–2001
Year
A/M + coloboma
A/M + cataract or aniridia/ PHPV
A/M + multiple congenital anomalies*
Chromosomal etiology
Syndrome or association
Total
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
0 2 1 1 0 0 0 0 1 1 0
1 1 0 0 0 0 1 0 2 0 0
3 1 4 0 0 0 1 2 0 3 2
2 3 0 0 2 1 2 0 5 3 2
0 1 3 0 1 0 2 2 1 2 1
6 8 8 1 3 1 6 4 9 9 5
Total
6
5
16
20
13
60
Rate per 10 000 total births (and 95% CI) 1.4 1.9 2.0 0.3 0.8 0.3 1.6 1.1 2.4 2.4 1.3
(0.5–3.0) (0.8–3.7) (0.9–3.9) (0.0–1.3) (0.2–2.2) (0.0–1.3) (0.6–3.5) (0.3–2.7) (1.1–4.5) (1.1–4.6) (0.4–3.1)
Source: ACASS. Note: PHPV = persistent hyperplastic primary vitreous. *Including holoprosencephaly.
worldwide over the past 3 decades (Table 3).2–8 Although some of the discrepancy may be due to actual differences, it is more likely due to different definitions, different diagnostic criteria and different ascertainment methods. Clearly, ascertainment up to 1 year or more, as in the ACASS, would be more complete than in registries and surveillance systems that are limited to a 7-day ascertainment period. In the extensive survey in Scotland a prevalence of 1.9/10 000 births was reported,2 but Campbell and colleagues,9 using a capture–recapture model, estimated that the completeness of ascertainment in this study was just over 60%; the model suggested that the true prevalence was considerably higher, possibly as high as 3.0/10 000. The inclusion or exclusion of chromosomal disorders makes a huge difference. Since A/M is a component of at least 40% of cases of trisomy 13, these disorders were excluded in the Scottish study2 and also in the study from England.5 The rate of A/M in Alberta in 1991–2001, 1.4/10 000 total births, is comparable to that in other registries, including the survey in Scotland.2 Unlike Morrison and associates,2 we did not include cases with isolated coloboma. Most investigators have listed cases with chromosomal anomalies separately, and some have given more details regarding associated congenital malformations and other eye defects3–8 (Table 3). Five cases of trisomy 13 were reported in Alberta in 1999. Note that pregnancy terminations were not included because the ACASS has been able to ascertain
such cases only since 1997. It is possible that there were additional cases of trisomy 13 in earlier years in which A/M defects either were not mentioned on the Congenital Anomaly Reporting Form or were not coded, as the ACASS was limited to six codes per case until 1997. As of 1997, as many anomalies can be coded as are reported; hence, changing ascertainment may be a factor in changing rates. Environmental causes, such as rubella, cytomegalic inclusion disease and toxoplasmosis, can cause A/M, but no such cases were found in our system. Congenital rubella is rare in Alberta since the introduction of rubella vaccine in childhood and verification of maternal rubella status in pregnancy. In the past there was a concern that maternal exposure to benomyl, a benzimidazole pesticide, might be responsible for A/M, but studies in England,5 Italy7,10 and Norway11 showed no support for this hypothesis, and the consensus of opinion in the International Clearinghouse for Birth Defects Monitoring Systems12 is that there is no association. Warburg has published a useful summary on the classification of microphthalmos and coloboma13 and a survey of genetic disorders associated with microphthalmos.14 Single-gene causes of A/M have been reported. Newer studies have shown that mutation of certain genes, including the developmental control genes PAX6,15,16 CHX10,17 SIX318 and SOX2,19 have been associated with A/M. PAX2 mutations have been associated with coloboma, either isolated or associated with urogenital anomalies.16 We have been unable to investigate
CAN J OPHTHALMOL—VOL. 40, NO. 1, 2005
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42
al4
CAN J OPHTHALMOL—VOL. 40, NO. 1, 2005 427 960
940 615
1.4
1.18
2.1
2.30
0.92
1.24
1.0
2.14
0.6 (anophthalmia only) 1.9 (A/M + coloboma)
A/M
0.14 (10.0) (including coloboma) 0.11 (8.3) (with associated eye anomalies)
0.40 (34.2)
NA
3.70 (16.1)
3.33 (36.3)
2.18 (17.5)
Not provided
0.2 (9.6)
Not provided
0.11 (9.1)
Isolated A/M
0.47 (33.3)
0.32 (27.0)
NA
6.62 (28.9)
0.68 (7.5)
3.02 (24.3)
Not provided
0.48 (22.5)
Not provided
0.22 (36.3)
A/M with chromosomal anomalies
0.45 (38.7) (including chromosomal anomalies) 0.68 (48.3) (excluding chromosomal anomalies) 1.14 (81.7) (including chromosomal anomalies)
NA
12.6 (54.9)
5.16 (56.2)
7.24 (58.2)
Not provided
1.93 (90.4)
32.8 (of cases examined)
0.54 (90.9)
A/M with multiple congenital anomalies
Cases ascertained to 1 year of age Included three pregnancy terminations Epidemiologic review included diverse eye anomalies Study performed to evaluate possible causal relation between benomyl and A/M
198 cases ascertained, 122 patients examined Age at examination not provided Holoprosencephaly and trisomy 13 excluded from definition of multiple congenital anomalies Definition of multiple congenital anomalies included holoprosencephaly, chromosomal anomalies and recognized syndromes Patients examined during first 3 days of life Cluster investigation Did not include cases of trisomy 13 or holoprosencephaly Study periods of three registries varied Chromosomal anomalies and other “associated eye anomalies” excluded from definition of multiple congenital anomalies
22 cases ascertained from hospital-based registry
Comments
*Rates of isolated A/M + multiple congenital anomalies + chromosomal anomalies may not equal the overall rate outlined in each study as chromosomal anomalies may be included under multiple congenital anomalies.
Note: NA = not available.
1991–2001
131 760
1979–88
Current study (Alberta)
2 054 842
1985–92
1986–90
2 191 790
1973–93
Spagnolo et al7 (Italy)
1 422 575
1978–93
Robert, in Källén et al6 (central-east France) Källén, in Källén et al6 (Sweden) Harris, in Källén et al6 (California) Stoll et al8 (Strasbourg, France)
4 538 790
1988–94
Dolk et al5 (England)
1 124 654
Not provided
1981–96
1980–95
368 256
Population
1981–89
Study period
Bermejo et al3 (Spain)
Clementi et (northeast Italy) Morrison et al2 (Scotland)
Investigator (and area)
Rate per 10 000 total births (and % of cases)
Table 3—Summary of review of literature on A/M*
Anophthalmia/microphthalmia—Lowry et al
Anophthalmia/microphthalmia—Lowry et al
any of our cases along these lines. Associated extraocular malformations are common and accounted for about 30% of cases in the series reported by Morrison and associates2 and 27% of cases in our series. No doubt many of these represent unique syndromes that remain to be identified. From time to time there are concerns about clustering of cases of A/M, but the many problems relating to this issue have been discussed.20,21 When one is dealing with small numbers, as is the case in Alberta, it is possible that higher rates are due to chance fluctuation or changing ascertainment or both.
CONCLUSION A review of A/M cases in Alberta confirmed that the rate for 1999 was high but that the increase was mainly due to five cases of trisomy 13 together with one case associated with Meckel–Gruber syndrome, leaving three cases of microphthalmia. The rate in 2000 was also high (2.4/10 000 births), but there were three cases with chromosomal abnormalities (trisomy 13 in two and trisomy 18 in one) and two cases associated with syndromes (Aicardi and Walker–Warburg), leaving three cases of microphthalmia with multiple congenital anomalies and one case of anophthalmia. In 2001 the rate decreased to 1.3/10 000: there were two cases with chromosomal abnormalities (trisomy 13 and triploidy), one case associated with a syndrome (ichthyosis) and two cases of microphthalmia with multiple extraocular anomalies, including holoprosencephaly in one case. Unfortunately, we were not able to compare the actual details of the cases in the CCASS. However, our review of the cases from the ACASS does provide reassurance that there was no environmental cause of clustering of anophthalmia or microphthalmia. Further work remains to be done to try to identify the syndromes of A/M with extraocular malformations and to further define the single-gene mutations that may be responsible. This review emphasizes the importance of ongoing population-based surveillance in providing baseline birth prevalence rates for evaluating trends and clusters. We acknowledge the administrative support and help of Dr. Stephan Gabos and Mr. Larry Svenson, of Alberta Health Surveillance, Alberta Health and Wellness, and of Dr. I.D. Rusen, of the Maternal and Infant Health Section, Health Surveillance and Epidemiology Division, Health Canada. We are grateful to Dr. Ian M. MacDonald for helpful suggestions. We thank Judy Anderson for secretarial assistance.
REFERENCES 1. International Clearinghouse for Birth Defects Monitoring Systems. Annual report 2003. Rome:
International Centre on Birth Defects; 2003. p. 39. 2. Morrison D, FitzPatrick D, Hanson I, Williamson K, van Heyningen V, Fleck B, et al. National study of microphthalmia, anophthalmia, and coloboma (MAC) in Scotland: investigation of genetic aetiology. J Med Genet 2002;39:16–22. 3. Bermejo E, Martínez-Frías ML. Congenital eye malformations: clinical–epidemiological analysis of 1,124,654 consecutive births in Spain. Am J Med Genet 1998;75: 497–504. 4. Clementi M, Turolla L, Mammi I, Tenconi R. Clinical anophthalmia: an epidemiological study in northeast Italy based on 368,256 consecutive births. Teratology 1992;46:551–3. 5. Dolk H, Busby A, Armstrong BG, Walls PH. Geographical variation in anophthalmia and microphthalmia in England, 1988–94. BMJ 1998;317:905–10. 6. Källén B, Robert E, Harris J. The descriptive epidemiology of anophthalmia and microphthalmia. Int J Epidemiol 1996;25:1009–16. 7. Spagnolo A, Bianchi F, Calabro A, Calzolari E, Clementi M, Mastroiacovo P, et al. Anophthalmia and benomyl in Italy: a multicenter study based on 940,615 newborns. Reprod Toxicol 1994;8:397–403. 8. Stoll C, Alembik Y, Dott B, Roth MP. Epidemiology of congenital eye malformations in 131,760 consecutive births. Ophthalmic Paediatr Genet 1992;13:179–86. 9. Campbell H, Holmes E, MacDonald S, Morrison D, Jones I. A capture–recapture model to estimate prevalence of children born in Scotland with developmental eye defects. J Cancer Epidemiol Prev 2002;7:21–8. 10. Bianchi F, Calabro A, Calzolari E, Mastroiacovo PP, Petrelli G, Spagnolo A, et al. Clusters of anophthalmia: no link with benomyl in Italy [letter]. BMJ 1994; 308:205. 11. Kristensen P, Irgens LM. Clusters of anophthalmia: no link with benomyl in Norway [letter]. BMJ 1994; 308:205–6. 12. Castilla EE. Clusters of anophthalmia: no further clues from global investigation [letter]. BMJ 1994;308:206. 13. Warburg M. Classification of microphthalmos and coloboma. J Med Genet 1993;30:664–9. 14. Warburg M. An update on microphthalmos and coloboma. A brief survey of genetic disorders with microphthalmos and coloboma. Ophthalmic Paediatr Genet 1991;12:57–63. 15. Glaser T, Jepeal L, Edwards JG, Young SR, Favor J, Maas RL. PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nat Genet 1994;7: 463–71; erratum 8:203. 16. Cunliffe HE, McNoe LA, Ward TA, Devriendt K, Brunner HG, Eccles MR. The prevalence of PAX2 mutations in patients with isolated colobomas or colobomas associated with urogenital anomalies. J Med Genet 1998;35:806–12. 17. Percin EF, Ploder LA, Yu JJ, Arici K, Horsford DJ, Rutherford A, et al. Human microphthalmia associ-
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ated with mutations in the retinal homeobox gene CHX10. Nat Genet 2000;25:397–401. 18. Wallis DE, Roessler E, Hehr U, Nanni L, Wiltshire T, Richieri-Costa A, et al. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet 1999;22:196–8. 19. Fantes J, Ragge NK, Lynch SA, McGill NI, Collin JR, Howard-Peebles PN, et al. Mutations in SOX2 cause anophthalmia. Nat Genet 2003;33(4):461–3.
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20. Cuzick J. Commentary: clustering of anophthalmia and microphthalmia is not supported by the data. BMJ 1998;317:910. 21. Mariman ECM. Clustering of anophthalmia and microphthalmia [editorial]. BMJ 1998;317:895–6. Key words: anophthalmia, microphthalmia, prevalence, epidemiology, surveillance
From *the Alberta Congenital Anomalies Surveillance System, Health Surveillance, Alberta Health and Wellness, Calgary, Alta., †the Department of Medical Genetics, Alberta Children’s Hospital/University of Calgary, Calgary, Alta., and ‡the Maternal and Infant Health Section, Health Surveillance and Epidemiology Division, Health Canada
Accepted for publication Aug. 11, 2004 Correspondence to: Dr. R. Brian Lowry, Department of Medical Genetics, Alberta Children’s Hospital, 1820 Richmond Rd. SW, Calgary AB T2T 5C7; fax (403) 228-0796; Brian.Lowry@calgary healthregion.ca
§Currently with Healthy Public Policy, Health Promotion/Disease Prevention, Calgary Health Region, Calgary, Alta.
This article has been peer-reviewed.
Originally received Jan. 23, 2004
Can J Ophthalmol 2005;40:38–44
38
Anophthalmia/microphthalmia—Lowry et al
Anophthalmia/microphthalmia—Lowry et al
This review demonstrates the importance of ongoing population-based surveillance in providing baseline birth prevalence rates for evaluating trends and clusters. x Contexte : Un taux plus haut que prévu d’anophtalmie/microphtalmie (A/M) a été relevé en 1999 par l’Alberta Congenital Anomalies Surveillance System (ACASS) et le Réseau canadien de surveillance des anomalies congénitales (RCSAC). Comme cela ne correspondait pas aux résultats des 19 années précédentes, nous avons revu la situation pour voir si la hausse était réelle et, le cas échéant, en déceler les explications possibles. Méthodes : Nous avons examiné les dossiers des cas d’A/M relevés par l’ACASS de 1991 à 2001, de même que la documentation afférente à chacun (consultant, autopsie, analyse des chromosomes). En outre, nous avons communiqué avec les 91 ophtalmologistes de l’Alberta. Nous avons aussi écrit aux bureaux d’Edmonton et de Calgary de l’Institut national canadien pour les aveugles (INCA). Résultats : Soixante cas d’A/M ont été établis pendant la période étudiée. Des 88 ophtalmologistes actifs de la province, 21 (24 %) ont répondu, mais cette source n’a confirmé aucun nouveau cas. L’INCA n’a pas répondu. Nous avons constitué cinq catégories de phénotypes cliniques pour les 60 cas : 20 avaient une étiologie chromosomique, 13 avaient un syndrome ou une association reconnus, 16 avaient des malformations extra-oculaires, 5 avaient d’autres anomalies oculaires et 6 avaient une A/M seulement. Les interruptions de grossesse n’ont pas été incluses. Le taux plus élevé de 1999 était surtout attribuable à des cas d’étiologie chromosomique ou de syndrome ou association reconnus. Rien n’indiquait qu’un facteur tératogène avait causé un ensemble de cas d’A/M, car nos taux annuels étaient semblables à ceux des autres juridictions non seulement au Canada mais aussi dans d’autres pays. Interprétation : Notre revue a confirmé que le taux d’A/M de 1999 en Alberta était élevé, mais que la hausse était surtout attribuable à cinq cas de trisomie 13 avec un cas associé à un syndrome, celui de Meckel–Gruber. Nos constatations nous ont rassurés sur l’absence de causes environnementales pour un groupement de cas d’anophtalmie ou de microphtalmie. La revue démontre l’importance d’une surveillance démographique constante qui fournira les taux de base de prévalence à la naissance afin d’évaluer les tendances et les groupements.
I
n preparing statistics for congenital anomalies, we found a higher than expected rate of anophthalmia/ microphthalmia (A/M) for 1999 in the Alberta Congenital Anomalies Surveillance System (ACASS) and in the Canadian Congenital Anomalies Surveillance System (CCASS), 2.4 and 1.87 per 10 000 total births respectively. The CCASS, the national surveillance registry, is a passive system that obtains data from the Discharge Abstract Database of the Canadian Institute for Health Information. The ACASS is a semiactive provincial surveillance system with the ability to seek out further information from medical records and consultant and laboratory reports.
Most provincial rates for A/M for 1991–99 were approximately 1/10 000 total births, with four exceptions: Quebec, 1.6, Nova Scotia, 1.8, Newfoundland, 2.5, and Saskatchewan, 2.5 (Table 1). The rate for Canada for the same period was 1.2, and for Alberta, 1.0 in the CCASS and 1.3 in the ACASS. A review of the rates of A/M in the ACASS for the 19-year period 1980–98 showed that the rate per 10 000 varied from 0.3 to 2.1, the 19-year aggregate rate being 1.4. The rate of 2.4 in 1999 was therefore completely at variance with the previous 19 years (ratio of observed to expected: 1.714, p = 0.02). We performed a review to determine whether the increase was true and, if so, the possible explanation.
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Table 1—Rates of anophthalmia/microphthalmia (A/M) in Canada for 1991–99 by province/territory
Province/territory
No. of cases
Rate per 10 000 total births (and 95% CI)
Yukon Territory Northwest Territories British Columbia Alberta* Saskatchewan Manitoba Ontario Quebec New Brunswick Nova Scotia Prince Edward Island Newfoundland
0 1 46 36 30 17 123 126 10 7 0 13
0 0.9 1.1 1.0 2.5 1.2 0.9 1.6 1.3 1.8 0 2.5
Canada
409
1.2 (1.1–1.4)
(0.01–5.2) (0.8–1.5) (0.7–1.4) (1.7–3.6) (0.7–1.9) (0.8–1.1) (1.3–1.9) (0.6–2.3) (0.7–3.6) (1.3–4.2)
Source: Canadian Congenital Anomalies Surveillance System (CCASS), Health Canada. Note: CI = confidence interval. *The rates reported by the CCASS and the Alberta Congenital Anomalies Surveillance System (ACASS) can vary. The ACASS contains 46 cases for 1991–99, whereas the CCASS contains 36 cases.
METHODS We reviewed the Alberta cases of A/M for the period 1991–2001 by retrieving the actual Congenital Anomaly Reporting Form plus any accompanying attachments (e.g., ophthalmology or other consultant reports, autopsy report, chromosome reports). In addition, we wrote, emailed or faxed letters to all 91 registered ophthalmologists in Alberta, asking whether they had any unreported cases of A/M. We also wrote to the Edmonton and Calgary branches of the Canadian National Institute for the Blind (CNIB). Unfortunately, it was not possible to review the cases from the CCASS. In reviewing cases of A/M and attempting to assign etiology it is often impossible to be precise as to the cause because of the heterogeneity of the disorders. At times, anophthalmia and microphthalmia are difficult to distinguish without histologic or ultrasound examination. The definition used by the International Clearinghouse for Birth Defects Monitoring Systems states: “Anophthalmos/ microphthalmos: apparently absent or small eyes. Some normal adnexal elements and eyelids are usually present. In microphthalmia, the corneal diameter is usually less than 10 mm. and the antero-posterior diameter of the globe is less than 20 mm.”1 In actual practice we accept
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a clinician’s description of these features without measurement, but we recognize the problems of case definition and lack of standardization between studies. Anophthalmia and microphthalmia may have the same etiology, as an affected person may have anophthalmia in one eye and microphthalmia in the other. Optic fissure closure defects (i.e., coloboma) are also part of the A/M phenotype. In calculating the ratio of observed to expected cases we used the aggregate rate for 1980–98 as the baseline. Since this was deemed to be a quality-control survey and part of the provincial department of health mandate for surveillance, permission from the Conjoint Ethics Board of the University of Calgary was not required.
RESULTS Sixty cases of A/M were ascertained over the period 1991–2001. Of the 88 active ophthalmologists in the province, 21 (24%) replied. No new cases were ascertained from this source. No replies were received from the CNIB. We constructed five categories of clinical phenotypes for the 60 cases: 20 (33%) had a chromosomal etiology (trisomy 13 in 16 cases, and, in 1 case each, trisomy 18, triploidy, 6q minus and 3 deletion/inversion) (Table 2). In 13 cases there was a recognized syndrome or association (Aicardi, amniotic band, CHARGE, Gorlin–Cohen [frontometaphyseal dysplasia], complex I deficiency, Hallermann–Streiff, ichthyosis, Lenz, Meckel– Gruber, Nager acrofacial dysostosis, sebaceous nevus, VATER or Walker–Warburg). Sixteen cases (27%) were associated with extraocular malformations, including holoprosencephaly in four (normal chromosomes were present in three of the four). There were six cases of A/M plus coloboma and five cases with other eye anomalies (cataract and persistent hyperplastic primary vitreous in two, isolated cataract in two, and aniridia and corneal opacity in one). The 11 cases with ocular defects corresponded to a rate of 0.2/10 000 total births, with the other categories (chromosomal, syndromal and multiple congenital anomaly) having a rate of 1.2/10 000. The annual rates are shown in Table 2. Over this period the rate for Alberta was 1.4/10 000. There were no appreciable differences in birth weight or gestational age between the cases with and without normal chromosomes. However, mean maternal age was lower for the cases with an abnormal karyotype than for those with a normal karyotype (25.6 vs. 30.4 years). The increased rate of A/M in 1999 was statistically significant (ratio of observed to expected: 1.71, p = 0.02).
INTERPRETATION There is marked variation in reported rates of A/M
Anophthalmia/microphthalmia—Lowry et al
Table 2—A/M in Alberta, 1991–2001
Year
A/M + coloboma
A/M + cataract or aniridia/ PHPV
A/M + multiple congenital anomalies*
Chromosomal etiology
Syndrome or association
Total
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
0 2 1 1 0 0 0 0 1 1 0
1 1 0 0 0 0 1 0 2 0 0
3 1 4 0 0 0 1 2 0 3 2
2 3 0 0 2 1 2 0 5 3 2
0 1 3 0 1 0 2 2 1 2 1
6 8 8 1 3 1 6 4 9 9 5
Total
6
5
16
20
13
60
Rate per 10 000 total births (and 95% CI) 1.4 1.9 2.0 0.3 0.8 0.3 1.6 1.1 2.4 2.4 1.3
(0.5–3.0) (0.8–3.7) (0.9–3.9) (0.0–1.3) (0.2–2.2) (0.0–1.3) (0.6–3.5) (0.3–2.7) (1.1–4.5) (1.1–4.6) (0.4–3.1)
Source: ACASS. Note: PHPV = persistent hyperplastic primary vitreous. *Including holoprosencephaly.
worldwide over the past 3 decades (Table 3).2–8 Although some of the discrepancy may be due to actual differences, it is more likely due to different definitions, different diagnostic criteria and different ascertainment methods. Clearly, ascertainment up to 1 year or more, as in the ACASS, would be more complete than in registries and surveillance systems that are limited to a 7-day ascertainment period. In the extensive survey in Scotland a prevalence of 1.9/10 000 births was reported,2 but Campbell and colleagues,9 using a capture–recapture model, estimated that the completeness of ascertainment in this study was just over 60%; the model suggested that the true prevalence was considerably higher, possibly as high as 3.0/10 000. The inclusion or exclusion of chromosomal disorders makes a huge difference. Since A/M is a component of at least 40% of cases of trisomy 13, these disorders were excluded in the Scottish study2 and also in the study from England.5 The rate of A/M in Alberta in 1991–2001, 1.4/10 000 total births, is comparable to that in other registries, including the survey in Scotland.2 Unlike Morrison and associates,2 we did not include cases with isolated coloboma. Most investigators have listed cases with chromosomal anomalies separately, and some have given more details regarding associated congenital malformations and other eye defects3–8 (Table 3). Five cases of trisomy 13 were reported in Alberta in 1999. Note that pregnancy terminations were not included because the ACASS has been able to ascertain
such cases only since 1997. It is possible that there were additional cases of trisomy 13 in earlier years in which A/M defects either were not mentioned on the Congenital Anomaly Reporting Form or were not coded, as the ACASS was limited to six codes per case until 1997. As of 1997, as many anomalies can be coded as are reported; hence, changing ascertainment may be a factor in changing rates. Environmental causes, such as rubella, cytomegalic inclusion disease and toxoplasmosis, can cause A/M, but no such cases were found in our system. Congenital rubella is rare in Alberta since the introduction of rubella vaccine in childhood and verification of maternal rubella status in pregnancy. In the past there was a concern that maternal exposure to benomyl, a benzimidazole pesticide, might be responsible for A/M, but studies in England,5 Italy7,10 and Norway11 showed no support for this hypothesis, and the consensus of opinion in the International Clearinghouse for Birth Defects Monitoring Systems12 is that there is no association. Warburg has published a useful summary on the classification of microphthalmos and coloboma13 and a survey of genetic disorders associated with microphthalmos.14 Single-gene causes of A/M have been reported. Newer studies have shown that mutation of certain genes, including the developmental control genes PAX6,15,16 CHX10,17 SIX318 and SOX2,19 have been associated with A/M. PAX2 mutations have been associated with coloboma, either isolated or associated with urogenital anomalies.16 We have been unable to investigate
CAN J OPHTHALMOL—VOL. 40, NO. 1, 2005
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42
al4
CAN J OPHTHALMOL—VOL. 40, NO. 1, 2005 427 960
940 615
1.4
1.18
2.1
2.30
0.92
1.24
1.0
2.14
0.6 (anophthalmia only) 1.9 (A/M + coloboma)
A/M
0.14 (10.0) (including coloboma) 0.11 (8.3) (with associated eye anomalies)
0.40 (34.2)
NA
3.70 (16.1)
3.33 (36.3)
2.18 (17.5)
Not provided
0.2 (9.6)
Not provided
0.11 (9.1)
Isolated A/M
0.47 (33.3)
0.32 (27.0)
NA
6.62 (28.9)
0.68 (7.5)
3.02 (24.3)
Not provided
0.48 (22.5)
Not provided
0.22 (36.3)
A/M with chromosomal anomalies
0.45 (38.7) (including chromosomal anomalies) 0.68 (48.3) (excluding chromosomal anomalies) 1.14 (81.7) (including chromosomal anomalies)
NA
12.6 (54.9)
5.16 (56.2)
7.24 (58.2)
Not provided
1.93 (90.4)
32.8 (of cases examined)
0.54 (90.9)
A/M with multiple congenital anomalies
Cases ascertained to 1 year of age Included three pregnancy terminations Epidemiologic review included diverse eye anomalies Study performed to evaluate possible causal relation between benomyl and A/M
198 cases ascertained, 122 patients examined Age at examination not provided Holoprosencephaly and trisomy 13 excluded from definition of multiple congenital anomalies Definition of multiple congenital anomalies included holoprosencephaly, chromosomal anomalies and recognized syndromes Patients examined during first 3 days of life Cluster investigation Did not include cases of trisomy 13 or holoprosencephaly Study periods of three registries varied Chromosomal anomalies and other “associated eye anomalies” excluded from definition of multiple congenital anomalies
22 cases ascertained from hospital-based registry
Comments
*Rates of isolated A/M + multiple congenital anomalies + chromosomal anomalies may not equal the overall rate outlined in each study as chromosomal anomalies may be included under multiple congenital anomalies.
Note: NA = not available.
1991–2001
131 760
1979–88
Current study (Alberta)
2 054 842
1985–92
1986–90
2 191 790
1973–93
Spagnolo et al7 (Italy)
1 422 575
1978–93
Robert, in Källén et al6 (central-east France) Källén, in Källén et al6 (Sweden) Harris, in Källén et al6 (California) Stoll et al8 (Strasbourg, France)
4 538 790
1988–94
Dolk et al5 (England)
1 124 654
Not provided
1981–96
1980–95
368 256
Population
1981–89
Study period
Bermejo et al3 (Spain)
Clementi et (northeast Italy) Morrison et al2 (Scotland)
Investigator (and area)
Rate per 10 000 total births (and % of cases)
Table 3—Summary of review of literature on A/M*
Anophthalmia/microphthalmia—Lowry et al
Anophthalmia/microphthalmia—Lowry et al
any of our cases along these lines. Associated extraocular malformations are common and accounted for about 30% of cases in the series reported by Morrison and associates2 and 27% of cases in our series. No doubt many of these represent unique syndromes that remain to be identified. From time to time there are concerns about clustering of cases of A/M, but the many problems relating to this issue have been discussed.20,21 When one is dealing with small numbers, as is the case in Alberta, it is possible that higher rates are due to chance fluctuation or changing ascertainment or both.
CONCLUSION A review of A/M cases in Alberta confirmed that the rate for 1999 was high but that the increase was mainly due to five cases of trisomy 13 together with one case associated with Meckel–Gruber syndrome, leaving three cases of microphthalmia. The rate in 2000 was also high (2.4/10 000 births), but there were three cases with chromosomal abnormalities (trisomy 13 in two and trisomy 18 in one) and two cases associated with syndromes (Aicardi and Walker–Warburg), leaving three cases of microphthalmia with multiple congenital anomalies and one case of anophthalmia. In 2001 the rate decreased to 1.3/10 000: there were two cases with chromosomal abnormalities (trisomy 13 and triploidy), one case associated with a syndrome (ichthyosis) and two cases of microphthalmia with multiple extraocular anomalies, including holoprosencephaly in one case. Unfortunately, we were not able to compare the actual details of the cases in the CCASS. However, our review of the cases from the ACASS does provide reassurance that there was no environmental cause of clustering of anophthalmia or microphthalmia. Further work remains to be done to try to identify the syndromes of A/M with extraocular malformations and to further define the single-gene mutations that may be responsible. This review emphasizes the importance of ongoing population-based surveillance in providing baseline birth prevalence rates for evaluating trends and clusters. We acknowledge the administrative support and help of Dr. Stephan Gabos and Mr. Larry Svenson, of Alberta Health Surveillance, Alberta Health and Wellness, and of Dr. I.D. Rusen, of the Maternal and Infant Health Section, Health Surveillance and Epidemiology Division, Health Canada. We are grateful to Dr. Ian M. MacDonald for helpful suggestions. We thank Judy Anderson for secretarial assistance.
REFERENCES 1. International Clearinghouse for Birth Defects Monitoring Systems. Annual report 2003. Rome:
International Centre on Birth Defects; 2003. p. 39. 2. Morrison D, FitzPatrick D, Hanson I, Williamson K, van Heyningen V, Fleck B, et al. National study of microphthalmia, anophthalmia, and coloboma (MAC) in Scotland: investigation of genetic aetiology. J Med Genet 2002;39:16–22. 3. Bermejo E, Martínez-Frías ML. Congenital eye malformations: clinical–epidemiological analysis of 1,124,654 consecutive births in Spain. Am J Med Genet 1998;75: 497–504. 4. Clementi M, Turolla L, Mammi I, Tenconi R. Clinical anophthalmia: an epidemiological study in northeast Italy based on 368,256 consecutive births. Teratology 1992;46:551–3. 5. Dolk H, Busby A, Armstrong BG, Walls PH. Geographical variation in anophthalmia and microphthalmia in England, 1988–94. BMJ 1998;317:905–10. 6. Källén B, Robert E, Harris J. The descriptive epidemiology of anophthalmia and microphthalmia. Int J Epidemiol 1996;25:1009–16. 7. Spagnolo A, Bianchi F, Calabro A, Calzolari E, Clementi M, Mastroiacovo P, et al. Anophthalmia and benomyl in Italy: a multicenter study based on 940,615 newborns. Reprod Toxicol 1994;8:397–403. 8. Stoll C, Alembik Y, Dott B, Roth MP. Epidemiology of congenital eye malformations in 131,760 consecutive births. Ophthalmic Paediatr Genet 1992;13:179–86. 9. Campbell H, Holmes E, MacDonald S, Morrison D, Jones I. A capture–recapture model to estimate prevalence of children born in Scotland with developmental eye defects. J Cancer Epidemiol Prev 2002;7:21–8. 10. Bianchi F, Calabro A, Calzolari E, Mastroiacovo PP, Petrelli G, Spagnolo A, et al. Clusters of anophthalmia: no link with benomyl in Italy [letter]. BMJ 1994; 308:205. 11. Kristensen P, Irgens LM. Clusters of anophthalmia: no link with benomyl in Norway [letter]. BMJ 1994; 308:205–6. 12. Castilla EE. Clusters of anophthalmia: no further clues from global investigation [letter]. BMJ 1994;308:206. 13. Warburg M. Classification of microphthalmos and coloboma. J Med Genet 1993;30:664–9. 14. Warburg M. An update on microphthalmos and coloboma. A brief survey of genetic disorders with microphthalmos and coloboma. Ophthalmic Paediatr Genet 1991;12:57–63. 15. Glaser T, Jepeal L, Edwards JG, Young SR, Favor J, Maas RL. PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nat Genet 1994;7: 463–71; erratum 8:203. 16. Cunliffe HE, McNoe LA, Ward TA, Devriendt K, Brunner HG, Eccles MR. The prevalence of PAX2 mutations in patients with isolated colobomas or colobomas associated with urogenital anomalies. J Med Genet 1998;35:806–12. 17. Percin EF, Ploder LA, Yu JJ, Arici K, Horsford DJ, Rutherford A, et al. Human microphthalmia associ-
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ated with mutations in the retinal homeobox gene CHX10. Nat Genet 2000;25:397–401. 18. Wallis DE, Roessler E, Hehr U, Nanni L, Wiltshire T, Richieri-Costa A, et al. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet 1999;22:196–8. 19. Fantes J, Ragge NK, Lynch SA, McGill NI, Collin JR, Howard-Peebles PN, et al. Mutations in SOX2 cause anophthalmia. Nat Genet 2003;33(4):461–3.
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20. Cuzick J. Commentary: clustering of anophthalmia and microphthalmia is not supported by the data. BMJ 1998;317:910. 21. Mariman ECM. Clustering of anophthalmia and microphthalmia [editorial]. BMJ 1998;317:895–6. Key words: anophthalmia, microphthalmia, prevalence, epidemiology, surveillance