Hereditary vision pathologies in children affect all ocular structures. Although of a varying degree of severity, they all impact the sense considered most sacred, justifying the intense amount of research that has been undertaken over the past three decades. A great deal of progress has been made, whether in terms of severe malformations of the anterior chamber or degenerative and inexorably developing pathologies of the retina. This progress has resulted in better genetic advice for families and, for the severest pathologies, which are often the least accessible for treatment, it has opened the door to prenatal diagnosis in the families affected. Finally, knowledge of the physiopathology of a large number of these diseases means that today, therapeutic approaches can be envisaged that will have a profound impact on the care given to patients.

Introduction

At the start of this 21st century, there would appear to be a strong increase in the number of ophthalmological pathologies of genetic origin in industrialised countries. But this increase is only relative. It is the result of two contrary events. The first is the spectacular reduction in acquired, particularly infectious, pathologies. The second is a better knowledge of genetically determined disorders, made possible in large part by the creation, in the eighties, of the gene map. This marked the start of an explosion in genome investigation methods, where continued progress has resulted in the identification of a considerable number of genes whose mutations cause severe sight disorders in children.

The development, maintenance, and functioning of ocular structures require the contribution of thousands of genes whose expression varies over time and is influenced, in part, by the environment. Mutations of these genes can be silent. But they are most often responsible for a change in visual performance that can go as far as total blindness (Table 1).

1. Development abnormalities

The most severe ophthalmological disorders are frequently caused by mutations affecting the genes involved in the development of ocular structures.

Sometimes unilateral, often bilateral, eye development abnormalities can occur at different stages in embryonic life, leading to a spectrum of malformations that can affect all structures of the eye, one by one, or together.

Anophthalmia, the most serious of these disorders, is characterised by total absence of any kind of ocular structure, resulting from an absence of induction of the optical vesicle, three weeks into embryonic life. Sometimes in isolation (primary anophthalmia), it is often correlated with more extensive malformation of the anterior brain (secondary anophthalmia).

Microphthalmia, is often characterised by a wide spectrum of severity, from the most extreme forms, often confused with anophthalmia, through to a small size eye, sometimes formed and operational, depending on whether the abnormality occurs during invagination of the optical vesicle, closure of the embryonic fissure or, later, due to halting of the development of the ocular structures that have been formed normally.

These early and severe malformations, the incidence of which is around 1 to 2 per 100 000 births, can be screened by ultra-sound at around 18-20 weeks of amenorrhoea. The sudden discovery of this type of malformation in a foetus born of healthy parents can be a sign of the occurrence of a dominant Novo mutation, often in a gene that programmes the eye, or of a rare autosomal recessive abnormality, particularly in blood-related couples. If abortion is chosen due to a bilateral blindness pathology, a foetal-pathological study should be requested, to search for associated malformations. In all cases, a genetic study will be offered to identify the mutation or mutations responsible, in order to offer an early molecular diagnosis for the next pregnancy, in case of genetic risk. Knowledge of the numerous genes responsible for these diseases is still only shaky, and genetic abnormalities cannot be discovered in every case.

Alongside these extreme forms, affecting the size and structure of the eye, there exists a variety of malformations of the anterior chamber, often the result of an abnormality in the migration of cells from the neural crest. These cases of iridocorneal dysgenesis, the prevalence of which is around 1 to 2 per 100 000 come in a wide anatomic spectrum, all with the same risk of occurrence of sudden, massive glaucoma making them very severe and necessitating regular monitoring of ocular pressure in all babies with these malformations. An examination should be performed several times a year under general anaesthetic in very young children under three. These cases of dysgenesis of the anterior segment are almost all inherited with autosomal dominance. A large number of genes have been identified, which unfortunately, does not cover all cases. Note that gene PAX6 is the major gene in ocular development, the mutations of which are responsible for a large number of malformations.

Primitive congenital glaucoma, the incidence of which is estimated at 5 for every 100 000 births, is the result of a cessation in the development of the iridocorneal angle at a stage corresponding to 6 months of intra-uterine life. It is then obstructed by thick trabecular meshwork that can lead, in utero, to ocular hypertension and buphthalmos that is visible during antenatal ultrasound screening. Nevertheless, a large number of these children are born with a normal-sized eye, even though at birth a megalocornea can already be observed. These children must receive an emergency operation (new-born, less than one week old) in order to release the iridocorneal angle. Primitive congenital glaucoma is a recessive autosomal malformation. The mutations of several genes may be responsible for it. Note, however, that the gene CYP1B1 alone represents 2/3 of cases.

Corneal dystrophies are extremely varied in terms of their anatomical presentation. The classification has been vastly improved by identification of a major gene, BIGH3, for which there exist genotype-phenotype correlations. All methods of transmission can be shown, but these afflictions, which caused blindness in the past, have seen their prognosis considerably improved by the development of corneal grafts. Corneal dystrophies are rare afflictions, the frequency of which has not been established with any degree of precision.

Congenital cataracts also vary greatly in terms of their clinical presentation. After excluding acquired ante- and neo-natal causes, all methods of transmission can be envisaged, with a majority of autosomal dominant forms which should not be neglected in the face of a sporadic case. The incidence of congenital cataracts is around 1 to 6 for 10 000 births. Numerous genes have been identified, the mutations of which are responsible for these opacities of the crystalline lens. Nevertheless, success in terms of the progress made with early surgical procedures (newborns less than a month old), involving a crystalline lens implant, has considerably reduced requests for genetic studies. Note, that most congenital cataracts are observed in utero enabling access to paediatric surgery in good conditions.

In terms of the posterior segment, two major categories of vision disorders can be distinguished: those resulting from a lack of normal retinal development and the large group of retinal degenerations.

With regard to the former, we will address only persistent primary vitreous, Stickler syndrome, juvenile retinoschisis linked to chromosome X, and Norrie disease.

Persistent primary vitreous is in most cases, unilateral and is not considered the result of any kind of transmissible genetic abnormality. Nevertheless, heredity is suspected but not elucidated in bilateral forms. The incidence of these affections is estimated at 1 in 30 000 births.

Stickler syndrome is an affliction whose frequency is around 1 to 5 per 10 000. It combines alterations in the vitreous evolving towards retinal detachment in childhood, accompanied by facial dysmorphia, bone dysplasia and, in some cases, hearing problems. It is always a dominant, autosomal affliction of variable expressivity. Three collagen genes have now been identified, covering almost all cases. In children with such illnesses, monitoring of the retinal periphery is necessary with barrage laser treatment if required. The severity of this disease and the possibility of prior identification of the mutation that causes it to mean that prenatal diagnosis is possible if families ask for it.

Juvenile retinoschisis linked to X refers to the association of maculopathy and a secondary vitreoretinopathy with the abnormal splitting of the retina in its innermost layer. It comes in the form of a bilateral cystic macular lesion and, on the periphery, a lifting (schisis) accompanied by blurring and vitreous condensation again representing the risk of retinal detachment. Diagnosis is not easy, but once done, the discovery of mutation by the only gene responsible, RS1, confirms the diagnosis and enables the screening of female carriers in the family. The prevalence of this affection varies according to populations between 1 in 5000 and 1 in 25 000.

Norrie disease, also linked to chromosome X, is rare (< 1 in 100 000). It designates major dysplasia of the retina and presents in a newborn as a leukocoria, due to the appearance of the retina as a highly vascularized white-yellowish mass which, in the past, could have been mistaken for a retinal tumour. This is a fearsome disease since consistently blinding retinal dysplasia is accompanied in 2/3 of cases by mental disability and in 1/3 of cases by developing deafness. Underlying this disease in all cases are mutations of the gene NDP. In cases where these mutations are recognised, they allow for screening of carriers in the family and prenatal diagnosis in women at risk.

2. Early-onset and severe degenerative retinal disorders

These refer to the gradual death of the photoreceptor – pigmentary epithelium couple and are extremely heterogenic from a clinical and genetic point of view. They can begin at any time of life, and many forms begin in the first two decades of life. Taking all forms into account, they affect one person in 3000.

These are inexorably evolutive diseases, which have a considerable impact on the visual function of the children involved.

Five major clinical groups of retinal degeneration can be distinguished, identifiable by the natural history of the diseases, their age, and how they started and their development.

The most frequent are rod-cone dystrophies (66% of retinal dystrophies), recognisable by a primary affliction of the rods resulting in problems with night vision and a concentric reduction in the peripheral field of vision. This impact on the rods will continue, 10 to 20 years later, with an impact on the function of the cones, recognisable by intolerance to light, dyschromatopsia and a reduction in visual acuity. These diseases are extraordinarily heterogeneous from a genetic point of view. Several dozen genes have already been identified, which cover 50% of cases.

Conversely, there are forms of cone-rod dystrophies (10-15% of retinal dystrophies), in which the first symptoms are primary disorders of the cones, which will be followed by a secondary affliction of the rods. The same genetic heterogeneity has been reported.

Isolated cone dystrophies are much rarer (2-3 % of retinal dystrophies), because when they are diagnosed, they may correspond to the initial stage of cone-rod dystrophies.

Leber Congenital Amaurosis (LCA) was for many years described as a separate entity. It is recognisable in the first weeks or months of life in new-borns with apparent blindness. It accounts for around 5-10% of all retinal dystrophies. This disease is autosomal recessive in almost all cases, based on the mutations of 17 different genes that cover only 70% of cases, certain of which have brought this type of blindness into the big group of ciliopathies (Fig. 1, 2). Genetic work carried out over the past 15 years has identified two major clinical types: a cone-rod type (type 1), which is dramatically severe and stationary and a rod-cone type (type 2) which is indeed severe but which evolves, representing the extremity of a spectrum of the seriousness of retinal dystrophies. Of these 17 genes, at least four accounts for type 1 LCA, which is still the most frequently observed, whereas around 12 account for type 2. The mutations of the latter can also account for later onset rod-cone type retinal dystrophies (Fig. 3).

Macular dystrophies are characterised by degeneration of the macular pigmentary epithelium, leading to the gradual death of central photoreceptors, the first of which is the cones. Within this group, Stargardt’s disease is by far the most frequent of all juvenile macular degenerations since it accounts alone for almost 10% of retinal dystrophies. Paradoxically, this disease is homogenous from a genetic point of view, despite its great clinical variability. Contrary to all other macular degenerations, which are autosomal dominant, Stargardt’s disease is consistently recessive. It is caused by mutations of the ABCA4 gene, the severity of which is closely correlated to that of the ensuing retinal disease.

Conclusion

The rapid discoveries that have been made in less than twenty years with regard to all these diseases have swept away the former dogma of “one gene, one disease” because today numerous diseases, even those that are extremely homogenous on a clinical level, can be caused by the mutations of very different genes (tissular expression and function) and, conversely, the mutations of one gene can be responsible for considerably different pathologies. One may have thought that the identification of the same gene in different pathologies would lead to the establishment of correlations between mutations and phenotype. Yet, with the exception of a few examples, particularly Stargardt’s disease and, to a lesser extent, Leber congenital amaurosis, this is not the case. This ignorance of the causes of phenotype variability, which is sometimes found even amongst siblings, calls genetic and environmental modifying factors into question. Definition of the complete genotype of individuals, technically possible today but too expensive to be realistic on a routine basis, should enable us in the years to come to find answers to the origins of this variability which is, without a doubt, one of the major future challenges that genetics will have to face.

References 

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Adams NA, Awadein A, Toma HS. The retinal ciliopathies. Ophthalmic Genet. 2007 Sep;28(3):113-25. Review.

Aldave AJ. The genetics of the corneal dystrophies. Dev Ophthalmol. 2011;48:51- 66. Epub 2011 Apr 26. Review.

Bardakjian TM, Schneider A. The genetics of anophthalmia and microphthalmia. Curr Opin Ophthalmol. 2011 Sep;22(5):309-13.

Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010 Sep;29(5):335-75. Epub 2010 Mar 31. Review.

Calvas P, Dufier JL. Anomalies du développement de l’oeil. in OEil et Génétique pp 63-74, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rue Camille

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Dollfus H, Dufier JL. Rétinopathies pigmentaires et principaux syndrome associés. in OEil et Génétique pp 243-260, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rue Camille Desmoulins, 92789 Issy-les-Moulineaux Cedex 9. Mai 2005. Dufier JL, Kaplan J, Puech B. Vitréorétinopathies in OEil et Génétique pp 187-211, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rueCamille Desmoulins, 92789 Issy-les-Moulineaux Cedex 9. Mai 2005.

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Goodwin P. Hereditary retinal disease. Curr Opin Ophthalmol. 2008 May;19(3):255- 62. Review.

Hamel C. Retinitis pigmentosa. Orphanet J Rare Dis. 2006 Oct 11;1:40. Review.

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Kokotas H, Petersen MB. Clinical and molecular aspects of aniridia. Clin Genet. 2010 May;77(5):409-20. Epub 2010 Jan 6. Review.

Michaelides M, Hardcastle AJ, Hunt DM, Moore AT. Progressive cone and cone-rod dystrophies: phenotypes and underlying molecular genetic basis. Surv Ophthalmol. 2006 May-Jun;51(3):232-58. Review.

Møller HU, Weiss JS. IC3D classification of corneal dystrophies. Dev Ophthalmol. 2011;48:1-8. Epub 2011 Apr 26. Review.

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Genetics of anterior segment dysgenesis disorders. Curr Opin Ophthalmol. 2011 Sep;22(5):314-24. Roche O, Keita Sylla F, Beby F, Orssaud C, Dufier JL. Persistence and hyperplasia of primary vitreous.

J Fr Ophtalmol. 2007 Jun;30(6):647-57. Review. French. Roche O. Altérations du cristallin et de la zonule. in OEil et Génétique pp 187-211, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rue Camille Desmoulins, 92789 Issy-les-Moulineaux Cedex 9. Mai 2005. Royer G, Hanein S, Raclin V, Gigarel N, Rozet JM, Munnich A, Steffann J, Dufier JL, Kaplan J, Bonnefont JP.

NDP gene mutations in 14 French families with Norrie disease. Hum Mutat. 2003 Dec;22(6):499. Rozet JM, Kaplan J.

Maladies de Stargardt et dystrophies rétiniennes liées au gène ABCA4 (ABCR). in OEil et Génétique pp 303-312, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rue Camille Desmoulins, 92789 Issy-les-Moulineaux Cedex 9. Mai 2005. Sergouniotis PI, Davidson AE, Mackay DS, Li Z, Yang X, Plagnol V, Moore AT, Webster AR.

Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis. Am J Hum Genet. 2011 Jul 15;89(1):183-90. Sikkink SK, Biswas S, Parry NR, Stanga PE, Trump D. X-linked retinoschisis: an update. J Med Genet. 2007 Apr;44(4):225-32. Epub 2006 Dec 15. Review.

Stone EM, Cideciyan AV, Aleman TS, Scheetz TE, Sumaroka A, Ehlinger MA, Schwartz SB, Fishman GA, Traboulsi EI, Lam BL, Fulton AB, Mullins RF, Sheffield VC, Jacobson SG. Variations in NPHP5 in patients with nonsyndromic leber congenital amaurosis and Senior-Loken syndrome. Arch Ophthalmol. 2011 Jan;129(1):81-7. Verma AS, Fitzpatrick DR.Anophthalmia and microphthalmia. Orphanet J Rare Dis. 2007 Nov 26;2:47. 

Abitbol M, Menasche M, Dufier JL. Gènes Majeurs du développement de l’oeil. in OEil et Génétique pp 45-61, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rue Camille Desmoulins, 92789 Issy-les-Moulineaux Cedex 9. Mai 2005.

Adams NA, Awadein A, Toma HS. The retinal ciliopathies. Ophthalmic Genet. 2007 Sep;28(3):113-25. Review.

Aldave AJ. The genetics of the corneal dystrophies. Dev Ophthalmol. 2011;48:51- 66. Epub 2011 Apr 26. Review.

Bardakjian TM, Schneider A. The genetics of anophthalmia and microphthalmia. Curr Opin Ophthalmol. 2011 Sep;22(5):309-13.

Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010 Sep;29(5):335-75. Epub 2010 Mar 31. Review.

Calvas P, Dufier JL. Anomalies du développement de l’oeil. in OEil et Génétique pp 63-74, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rue Camille Desmoulins, 92789 Issy-les-Moulineaux Cedex 9. Mai 2005.

Dollfus H, Dufier JL. Rétinopathies pigmentaires et principaux syndrome associés. in OEil et Génétique pp 243-260, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rue Camille Desmoulins, 92789 Issy-les-Moulineaux Cedex 9. Mai 2005.

Dufier JL, Kaplan J, Puech B. Vitréorétinopathies in OEil et Génétique pp 187-211, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rue Camille Desmoulins, 92789 Issy-les-Moulineaux Cedex 9. Mai 2005.

Dufier JL, Kaplan J. Glaucomes congénitaux primitifs et secondaires dysgénésiques. in Oeil et Génétique pp 159-177, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rue Camille Desmoulins, 92789 Issy-les-Moulineaux Cedex 9. Mai 2005.

Girgis N, Chen TC. Genetics of the pediatric glaucomas. Int Ophthalmol Clin. 2011 Summer;51(3):107-17. Review.

Goodwin P. Hereditary retinal disease. Curr Opin Ophthalmol. 2008 May;19(3):255- 62. Review.

Hamel C. Retinitis pigmentosa. Orphanet J Rare Dis. 2006 Oct 11;1:40. Review.

Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007 Feb 1;2:7. Review.

Huang B, He W. Molecular characteristics of inherited congenital cataracts. Eur J Med Genet. 2010 Nov-Dec;53(6):347-57. Epub 2010 Sep 17. Review.

Kaplan J, Dufier JL. Amaurose congénitale de Leber. in OEil et Génétique pp 261- 271, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rue Camille Desmoulins, 92789 Issy-les-Moulineaux Cedex 9. Mai 2005.

Kaplan J.Leber congenital amaurosis: from darkness to spotlight. Ophthalmic Genet. 2008 Sep;29(3):92-8.

Kokotas H, Petersen MB. Clinical and molecular aspects of aniridia. Clin Genet. 2010 May;77(5):409-20. Epub 2010 Jan 6. Review.

Michaelides M, Hardcastle AJ, Hunt DM, Moore AT. Progressive cone and cone-rod dystrophies: phenotypes and underlying molecular genetic basis. Surv Ophthalmol. 2006 May-Jun;51(3):232-58. Review.

Møller HU, Weiss JS. IC3D classification of corneal dystrophies. Dev Ophthalmol. 2011;48:1-8. Epub 2011 Apr 26. Review.

Moore AT. Childhood macular dystrophies. Curr Opin Ophthalmol. 2009 Sep;20(5):363-8. Review.

Munier F, Schorderet D, Uffer S. Dystrophies héréditaires de la cornée. in OEil et Génétique pp 139-158, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rue Camille Desmoulins, 92789 Issy-les-Moulineaux Cedex 9. Mai 2005.

Perrault I, Hanein S, Gerard X, Delphin N, Fares-Taie L, Gerber S, Pelletier V, Mercé E, Dollfus H, Puech B, Defoort-Dhellemmes S, Petersen MD, Zafeiriou D, Munnich A, Kaplan J, Roche O, Rozet JM. Spectrum of SPATA7 mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum Mutat. 2010 Mar;31(3):E1241-50.

Puech B. Dystrophies maculaires hérédiatires. in OEil et Génétique pp 273-301, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rue Camille Desmoulins, 92789 Issy-les-Moulineaux Cedex 9. Mai 2005.

Reis LM, Semina EV. Genetics of anterior segment dysgenesis disorders. Curr Opin Ophthalmol. 2011 Sep;22(5):314-24.

Roche O, Keita Sylla F, Beby F, Orssaud C, Dufier JL. Persistence and hyperplasia of primary vitreous. J Fr Ophtalmol. 2007 Jun;30(6):647-57. Review. French.

Roche O. Altérations du cristallin et de la zonule. in OEil et Génétique pp 187-211, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rue Camille Desmoulins, 92789 Issy-les-Moulineaux Cedex 9. Mai 2005.

Royer G, Hanein S, Raclin V, Gigarel N, Rozet JM, Munnich A, Steffann J, Dufier JL, Kaplan J, Bonnefont JP. NDP gene mutations in 14 French families with Norrie disease. Hum Mutat. 2003 Dec;22(6):499.

Rozet JM, Kaplan J. Maladies de Stargardt et dystrophies rétiniennes liées au gène ABCA4 (ABCR). in OEil et Génétique pp 303-312, Société Française d’Ophtalmologie, Editions Masson S.A.S. 21, rue Camille Desmoulins, 92789 Issy-les-Moulineaux Cedex 9. Mai 2005.

Sergouniotis PI, Davidson AE, Mackay DS, Li Z, Yang X, Plagnol V, Moore AT, Webster AR. Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis. Am J Hum Genet. 2011 Jul 15;89(1):183-90.

Sikkink SK, Biswas S, Parry NR, Stanga PE, Trump D. X-linked retinoschisis: an update. J Med Genet. 2007 Apr;44(4):225-32. Epub 2006 Dec 15. Review.

Stone EM, Cideciyan AV, Aleman TS, Scheetz TE, Sumaroka A, Ehlinger MA, Schwartz SB, Fishman GA, Traboulsi EI, Lam BL, Fulton AB, Mullins RF, Sheffield VC, Jacobson SG. Variations in NPHP5 in patients with nonsyndromic leber congenital amaurosis and Senior-Loken syndrome. Arch Ophthalmol. 2011 Jan;129(1):81-7.

Verma AS, Fitzpatrick DR. Anophthalmia and microphthalmia. Orphanet J Rare Dis. 2007 Nov 26;2:47.