Fetal Colobomas

Coloboma is a rare eye malformation that affects 1,4/10,000 births (1). It refers to the absence of normal tissue in the central part of the eye. It is an important cause of visual impairment in children. It can be isolated or associated with one of more genetic syndromes (2,3). 

ICD Code: Q13.0

This anomaly is responsible of major visual impairment for children.
 

The knowledge of embryology allows a good understanding of this condition. Eye development begins with the formation of the optic sulcus at 22 days’ gestation in the region of the future diencephalon. The cranial neuropore closes on day 24 and by this time the optic primordia have developed into lateral evaginations of the neural tube, the optic vesicles. The distal face of the optic vesicle (retinal disc) invaginates into the expanded tip of the optic vesicle to form the optic cup on day 31, which is connected to the brain via the optic stalk. Blood vessels access the interior of the optic cup through a fissure on its ventral surface: the choroidal fissure. The lips of the choroidal fissure fuse by day 37, and the persistence of a part of the choroidal fissure may be a cause of colobomas. Colobomas can occur in any part of the eyeball: eyelid, iris, retina, and optic nerve (4,5,6,7). 

To date, it seems impossible to diagnose colobomas of eyelid and iris prenatally, but the diagnosis of retinal or optic nerve colobomas is now feasible by ultrasound and MRI (8). The diagnosis of retinal coloboma is possible with 2D US, the axial plane allowing visualization of the retinal fundus; This allows visualization, at the bottom of the eyeball, of  a “notch” at the level of retina.  
           
In 2008 Bault and Quarello described a new diagnostic technique based on 3D US they called: “fetal virtual eyeground." A volume of the whole eyeball is acquired in a frontal plane of the fetal face, after the acquisition of the volume, a surface rendering mode is applied and the ‘Magicut’ tool is used to ‘erase’ the frontal part of the eyeball, allowing to visualize of the whole retina, in the manner of a post-natal funduscopic examination (9,10). Hanssens and al in 2016 (11), Egloff and al in 2020 each described 2 cases of coloboma using this technique (2). Rignini et al described 3 cases of coloboma at the junction of optic nerve and retina by using MRI (12). 
 
Colobomas of the optic nerve can also be visualized by 2D US. 
 
 Under which conditions is it important to look for a coloboma? 
•    If there a family history of ophthalmologic or polymalformative syndrome? 
•    When the fetus has microphthalmia?  
•    In cases where cysts are detected next or in front of the orbits on ultrasound? 
•    When there a suspicion of a certain eye syndrome? (3) 
•    Or systematic examination of the orbits (14). 
 

Colobomas can be isolated (44.4%) or part of a polymalformative syndrome (55.6%). Although they are most often unilateral (77.7%), bilateral cases have been reported. A bilateral coloboma should prompt the search for other elements of a polymalformative syndrome, present in 100% of the reported cases. Conversely, unilateral coloboma is more frequently reported as an isolated finding (57%) (3). 
 
A large proportion of sporadic, unilateral, cases are most likely due to non-genetic factors. Certain drugs such thalidomide, alcohol and maternal deficiency in vitamin A are likely involved in the non-closure of the choroid fissure (3).  Gregory-Evans et al demonstrated (3) that an extraordinary number of conditions are associated with coloboma, with over 300 entries found in OMIM at present, with different patterns of inheritance (AD, AR, and XL). The most known syndrome associated with coloboma is CHARGE, which includes coloboma, choanal atresia, heart anomalies, body growth delay, genitourinary anomalies, and ear anomalies (14). Righini et al first reported 2 cases of CHARGE in 2008 diagnosed by MRI (12). Chaoui et al., report 1 case in 2010 by 3D US (15) and Alby et al., 2 additional cases in 2012 by MRI (16). Aicardi syndrome, characterized mainly by female subjects with agenesis of the corpus callosum, heterotopias in the gray matter, interhemispheric cysts, and retinal lacunae choroid associated with severe neurological impairment and epilepsy, was suspected in one case by MRI (12).  

Congenital eye defects are rare and, their prognosis may be severe. Therefore, efforts should be made to detect them before birth by US (essentially 3D US) or MRI (16). Coloboma of the retina or optic nerve can be responsible for severe visual impairment or blindness. These malformations can be isolated or associated with other anomalies of the eye or midline and are often associated with genetic syndromes. 
 
 

1- Congenital eye malformations in 212,479 births Stoll C, Alembik Y, Dott B, Roth MP.. Ann Genet. 1997; 40:122-128 

2- C.EgloffabcM.TassinabcJ.P.BaultdA.BarjoleA.CollinfI.SimongJ.SibiudeabcL.MandelbrotabcO.Piconeabc Journal of Gynecology Obstetrics and Human ReproductionVol49, Issue 7, September 2020 101746 

3- Ocular coloboma: a reassessment in the age of molecular neuroscience. Gregory-Evans, C Y (2004). Journal of Medical Genetics, 2004 41(12), 881–891.

4- Onwochei BC, Simon JW, Bateman JB, Couture KC, Mir E.Ocular colobomata. Surv Ophthalmol 2000; 45: 175–194. 

5- The prenatal development of the optic fissure in colobomatous microphthalmia Hero I, Farjah M, Scholtz CL.. Invest Ophthalmol Vis Sci 1991 ; 32 : 2622–2635. 

6- Essentials of Human Embryology (3rd edn). Larsen WJ. Churchill Livingstone: New York, 2001. 

7- Robert-Barishak Y. Embryology of the Eye and its Adnexa (2nd edn). Karger: Basel, 2001. 

8-Brémond-Gignac D1, Copin H, Elmaleh M, Milazzo S. Fetal ocular anomalies: the advantages of prenatal magnetic resonance imaging. J Fr Ophtalmol. 2010 May;33(5):350-4 

9- P27.15: Retinal coloboma: a case report using “virtual eyeground”: A new technique to visualize the fetal retina with 3D ultrasound J. P. Bault Ultrasound in Obstetrics & Gynecology 11 August 2008 

10- Retinal coloboma: prenatal diagnosis using a new technique, the ‘virtual fetal eyeground’J.‐P. Bault, E. Quarello Ultrasound in Obstetrics & Gynecology 23 March 2009 

11- Prenatal diagnosis of retinal coloboma: interest of the three-dimensional ultrasonography. Sandy Hanssens, Capucine Coulon, Freddy Avni, Pascal Vaast, Veronique Debarge European Journal of Obstetrics & Gynecology and Reproductive Biology Volume 201, June 2016, Pages 219-220 

12- Prenatal magnetic resonance imaging of optic nerve head coloboma. Righini A, Avagliano L, Doneda C, Pinelli L, Parazzini C, Rustico M, Triulzi F, Bulfamante G. Prenat Diagn 2008; 28: 242–246 

13- Practice guidelines for performance of the routine mid-trimester fetal ultrasound scan  
L. J. Salomon, Z. Alfirevic, V. Berghella, C. Bilardo, E. Hernandez-Andrade, S. L. Johnsen, K. Kalache, K.-Y. Leung, G. Malinger, H. Munoz, F. Prefumo, A. Toi and W. Lee on behalf of the ISUOG Clinical Standards Committee. 

14- CHARGE syndrome: Report of 47 cases and review 
AMERICAN JOURNAL OF MEDICAL GENETICSVolume 76, Issue 5, 13 April 1998, Pages: 402–409, A.L. Tellier, V. Cormier-Daire, V. Abadie, J. Amiel, S. Sigaudy, D. Bonnet, P. de Lonlay-Debeney, M.P. Morrisseau-Durand, P. Hubert, J.L. Michel, D. Jan, H. Dollfus, C. Baumann, P. Labrune, D. Lacombe, N. Philip, M. LeMerrer, M.L. Briard, A. Munnich and S. Lyonnet 

15-P09.05: Prenatal diagnosis of a fetus with a CHARGE syndrome 
R. Chaoui, G. Thiel, A. Sarut Lopez, A. Bergann, K. S. Heling Ultrasound in Obstetrics & Gynecology 6 October 2010 

16-C. Alby-Averseng; N. Benzina; J. Bault; J. Stirnemann; N. E. Russell; P. Sonigo; A. Millischer; T. Attie Bitach; L. J. Salomon; Y. Ville (2012). P30.14: The role of prenatal ultrasound and MRI in the prenatal diagnosis of CHARGE: a single centre prenatal series of 10 cases of CHD7 mutated fetuses., 40(S1), doi:10.1002/uog.12199  
 

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