RETINAL ONCOLOGY CASE REPORTS IN OCULAR ONCOLOGY

SECTION EDITOR: CAROL L. SHIELDS, MD

Uveal Coloboma:
The Related
Syndromes
BY IRINA BELINSKY, MD; APARNA RAMASUBRAMANIAN, MD;
NEELEMA SINHA, MD; AND CAROL SHIELDS, MD

C oloboma is a term derived from a

Greek root, meaning mutilated or
curtailed.1 Optic nerve and retino-
choroidal coloboma are caused by
incomplete closure of the embryonic fissure
during fetal development.1 The incidence of
coloboma is reported per 10,000 births to be
0.5 in Spain, 0.7 in France, and 0.75 in China.2-4
When isolated, coloboma is most commonly
sporadic and can be inherited in an autosomal
dominant, autosomal recessive, and x-linked
recessive fashion.1 Its predominant association
with other congenital anomalies, however,
highlights the genetic heterogeneity of this
ocular malformation.
In this report, we discuss a family with mul-
tiple ocular malformations and emphasize the
various disorders associated with chorioretinal Figure 1. Patient 1. A 3-1/2-month old male presenting with
coloboma. strabismus and leukocoria was found to have bilateral chori-
oretinal colobomas. External photograph demonstrating
THREE CASES FROM ONE FAMILY right eye leukocoria and bilateral esotropia. There was no
Patient 1. A 3-1/2-month-old white male iris coloboma in either eye (A). Chorioretinal coloboma in
manifested left esotropia since birth. On the inferonasal quadrant of right eye measuring 10 x 9 mm
examination, visual acuity was fix-and-follow that involves the optic disc sparing the fovea (B).
in both eyes. Slit-lamp exam of both eyes dis- Chorioretinal coloboma in the inferonasal quadrant of left
closed bilateral leukocoria and 30 prism eye measuring 7 x 7 mm that involves the optic disc (C).
diopters of alternating esotropia (Figure 1A).
There was no iris or lens coloboma and no nystagmus. cleft lip and palate (Figure 2A) was noted to have nys-
Fundus evaluation revealed chorioretinal and optic tagmus from birth. Patient has a family history of
nerve coloboma with sparing of fovea in both eyes coloboma in her brother (Patient 1) and optic nerve
(Figures 1B and 1C). Genetic testing revealed CHD-7 hypoplasia in mother (Patient 3). On examination, the
missense mutation, but systemic evaluation with chest right eye was microphthalmic and had two coloboma-
x-ray, echocardiogram, and MRI was normal. At 1-year ta including a large optic nerve coloboma and a small-
follow-up, the colobomata were stable in size and er macular coloboma (Figure 2B). Ultrasound evalua-
there was no retinal detachment. tion revealed a small orbital cyst, contiguous with the
Patient 2. A 2-month-old white female, born with coloboma. In the left eye, there was a single coloboma

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 RETINAL ONCOLOGY CASE REPORTS IN OCULAR ONCOLOGY

ple congenital anomalies in

58%, and as part of a multisys-
tem syndrome in 27%.
The most important
coloboma-related syndromes
are listed below.
CHARGE Syndrome (Hall-
Hittner syndrome; OMIM
214800). This is the most com-
mon syndrome found in
patients with coloboma.5
CHARGE syndrome occurs in
almost 20% of patients with
uveal coloboma.6 CHARGE syn-
drome includes the following
features: coloboma, heart
defects, atresia (choanae), retar-
dation of growth and develop-
ment, genitourinary problems,
and ear anomalies. The inci-
Figure 2. Patient 2. A 2-month-old female presented with bilateral dence rate of CHARGE syn-
chorioretinal colobomas, microphthalmos with cyst, and a cleft lip and drome is 0.1 to 1.2 per 10,000
palate. External photograph demonstrating right eye microphthalmos live births.7
with esotropia and cleft lip (A). Right microphthalmic eye with two CHARGE syndrome is a clini-
colobomas: a large optic nerve coloboma measuring 11 x 10 mm and a cal diagnosis. An expert com-
macular coloboma measuring 10 x 6 mm (B). Single coloboma seen mittee in 1998 formulated the
inferonasally in the left eye measuring 19 mm in greatest diameter diagnostic criteria for CHARGE
with involvement of the optic disc and the edge of the fovea (C). syndrome. The major criteria
are the classic 4C’s, which
inferonasally involving the optic disc and the edge of include 1) choanal atresia, 2) coloboma, 3) charac-
the foveola (Figure 2C). Genetic testing confirmed teristic ears and 4) cranial nerve anomalies. The
CHD-7 missense mutation. MRI of the brain showed minor criteria include cardiovascular malformations,
that the brainstem, particularly the pons, was reduced genital hypoplasia, cleft lip/palate, tracheoe-
in size. sophageal fistula, CHARGE facies, growth deficiency
Patient 3. The mother of patients 1 and 2 is a 33- and developmental delay. Individuals with all four
year-old white female with a history of congenital major characteristics or three major and three minor
cataracts, optic nerve hypoplasia, and multiple strabis- characteristics are highly likely to have CHARGE syn-
mus surgeries. On examination, the patient was legally drome.8
blind and aphakic in both eyes. Fundus exam revealed Ophthalmic manifestations of CHARGE syn-
bilateral optic nerve hypoplasia. The patient’s brain drome include uveal coloboma, optic nerve
MRI was within normal limits. Genetic testing revealed hypoplasia, microphthalmia, anophthalmia, nys-
no chromosomal abnormalities. tagmus, strabismus, and refractive errors.9 In
regard to genetics, CHD7 (chromodomain heli-
DISCUSSION case DNA-binding protein) mutations are seen in
Coloboma results from the failure of the optic fis- two-thirds of cases.9
sure to close during the fifth to seventh week of ges- Renal Coloboma Syndrome (OMIM 120330). This
tation when the embryo corresponds to the 7-mm abnormality is associated with progressive renal
to 14-mm stage of development.1 The timing of the insufficiency needing dialysis and transplantation;
defect explains the multiple associations with sys- hence, early diagnosis is critical. Ophthalmic mani-
temic malformations. Bermejo and associates3 evalu- festations include coloboma of the optic nerve and
ated 55 eyes with coloboma and found that colobo- abnormal vascular pattern of the optic disc.10 The
ma occurred in isolation in 15% of cases, with multi- systemic manifestations include renal hypoplasia

40 I RETINA TODAY I MAY/JUNE 2010

 RETINAL ONCOLOGY CASE REPORTS IN OCULAR ONCOLOGY

Support provided by the Eye Tumor Research

Although they can occur in Foundation, Philadelphia, PA (CLS).
The authors have no financial interests to disclose.
isolation, colobomata are Irina Belinsky, MD, is a PGY-1 preliminary
commonly associated with medicine resident at California Pacific Medical
other congenital ocular and Center, San Francisco, CA, and will be doing
her residency in ophthalmology at New York
systemic anomalies. University/Manhattan Eye & Ear, New York,
NY. She can be reached via e-mail at
(leading to renal failure), vesicoureteral reflux, and irinabelinsky00@gmail.com.
sensorineural hearing loss.11 In regard to genetics, Aparna Ramasubramanian, MD, is fellow at
renal colobloma syndrome is autosomal dominant. the Ocular Oncology Service at Wills Eye
PAX2 gene mutations are seen in nearly 50% of Hospital, Thomas Jefferson University. She can
patients.12 be reached via e-mail at
Cat-eye syndrome (Schmid-Fraccaro syndrome; aparna.r.krishna@gmail.com.
OMIM 115470). Cat-eye syndrome is a rare disor- Neelema Sinha, MD, is a PGY-1 resident physi-
der with classical triad of iris coloboma, anal cian at UMDNJ-Robert Wood Johnson University
anomalies, and preauricular malformations. Its Hospital. She can be reached via e-mail atnnsin-
systemic manifestations include preauricular tags, ha81@gmail.com.
facial dysmorphism, anal atresia, congenital heart Carol L. Shields, MD, is the Co-Director of the
disease and urogenital malformation.13 Cat-eye Ocular Oncology Service, Wills Eye Hospital,
syndrome features a supernumerary chromosome Thomas Jefferson University. Dr. Shields is a
consisting of duplicated material of chromosome member of the Retina Today Editorial Board.
22.13 She may be reached at carol.shields@shieldson-
Kabuki syndrome (OMIM 147920). This is an cology. com; phone: +1 215 928 3105; fax:
autosomal dominant disorder that is important to +1 215 928 1140.
differentiate from CHARGE syndrome. Overlapping
systemic features with CHARGE syndrome are 1. Onwochei BC, Simon JW, Bateman JB, et al. Ocular colobomata. Surv Ophthalmol.
coloboma, cleft palate, heart defects, and growth 2000;45:175-194.
2. Lu BX. An analysis of 193 cases of congenital intraocular colobomas. Zhonghua Yan Ke
retardation. Unique features include long palpebral Za Zhi. 1989;25:357-359.
fissures with eversion of the lateral third of lower 3. Bermejo E, Martinez-Frias ML. Congenital eye malformations: clinical-epidemiological
eyelids, sparse eyebrows, and large ears.14 This char- analysis of 1,124,654 consecutive births in Spain. J Med Genet. 1998;75:497-504.
acteristic facies does not manifest until 2 to 4 years 4. Stoll C, Alembik Y, Dott B, Roth MP. Epidemiology of congenital eye malformations in
of age; hence, follow-up is essential to differentiate 131,760 consecutive births. Ophthalmic Paediatr Genet. 1992;13:179-186.
5. Chang L, Blain D, Bertuzzi S, Brooks BP. Uveal coloboma: clinical and basic science
CHARGE syndrome from Kabuki syndrome.14 The update. Curr Opin Ophthalmol. 2006;17:447-470.
genetic causes of Kabuki syndrome are unknown. 6. Ozeki H, Shirai S, Nozaki M, Ikeda K, Ogura Y: Maldevelopment of neural crest cells in
Miscellaneous syndromes. Other syndromes asso- patients with typical uveal coloboma. J Pediat Ophthalmol Strabismus. 1999;36:337-341.
ciated with coloboma include Walker-Warburg syn- 7. Blake KD, Issekutz KA, Smith IM, Prasad C, Graham JM Jr: The incidence and prevalence
drome, Noonan syndrome, linear sebaceous nevus of CHARGE syndrome. The CPSP annual report 2002 and 2003 [http://www.CPS.ca].
8. Blake KD, Davenport SLH, Hall BD, et al. CHARGE association: an update and review for
syndrome, focal dermal hypoplasia, Aicardi syn- the primary pediatrician. Clin Pediatr. (Phila). 1998;37:159-173.
drome, and Goldenhar syndrome.15 9. Sanlaville D, Verloes A. CHARGE syndrome: an update. Eur J Hum Genet. 2007; 15:389-399.
10. Bron AJ, Burgess SEP, Awdry PN, et al. Papillo-renal syndrome. An inherited association
SUMMARY of optic disc dysplasia and disease. Report and review of the literature. Ophthalmic Paediatr
We have described two cases of CHARGE syndrome Genet. 1989;10:185-198.
11. Schimmenti LA, Cunliffe HE, McNoe LA, et al. Further delineation of renal coloboma syn-
with documented CHD7 mutation in a brother and drome in patients with extreme variability of phenotype and identical PAX2 mutations. Am J
sister, whose presentations illustrate the phenotypic Hum Genet. 1997;60:869-878.
heterogeneity of this syndrome. Although they can 12. Dureau P, Attie-Bitach T, Salomon R, et al. Renal coloboma syndrome. Ophthalmology.
occur in isolation, colobomata are commonly associat- 2001;108:1912-1916.
ed with other congenital ocular and systemic anom- 13. Meins M, Burfeind P, Motsch S et al. Partial trisomy of chromosome 22 resulting from an inter-
stitial duplication of 22q11.2 in a child with typical cat eye syndrome. J Med Genet. 2003;40:e62.
alies. The diagnosis of coloboma by an ophthalmolo- 14. Ming JE, Russell KL, Bason L et al. Coloboma and other ophthalmologic anomalies in
gist should prompt a careful systemic workup and Kabuki syndrome: distinction from Charge association. Am J Med Genet. 2003;123A:249-252.
family history. ■ 15. Pagon RA. Ocular coloboma. Surv Ophthalmol. 1981;25:223.

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