Eye (199 1) 5, 470-475

The Systemic and Genetic Significance of Congenital Anomalies

M. JACOBS and D. TAYLOR London

Summary Optic disc anomalies have great significance as a clue to associated systemic prob­ lems and as a marker of inherited disease. hypoplasia and colobomas of the optic disc are the main visually significant disorders; however, the Morning Glory disc anomaly and Aicardi's syndrome may also be associated with .

The diagnosis of congenital optic disc anoma­ mental is thought to be lies is of great importance because of the gen­ associated with maternal diabetes.'!> etic and systemic implications. The The may vary from near ophthalmologist has the opportunity of being normal (6/9) to no light perception.' Severe the first to diagnose an underlying disease or optic nerve hypoplasia is easily appreciated syndrome and referring patients for genetic but the more subtle forms are more difficultto and paediatric assessment. It is of equal sig­ diagnose even with direct .' nificance to parents that some optic nerve Diagnosis is essentially clinical but the diag­ anomalies are not associated with inherited nosis may be aided by further studies. Firstly, disease. Peripapillary myelinated nerve fibres diagnosis can be enhanced by comparing the and optic disc which are not usually ratio of the major blood vessel diameter to the associated with systemic conditions are not diameter of the optic disc, and secondly by discussed. studying the ratio of the disc centre-to-fovea distance (DM) to disc diameter (DD) from a Optic Nerve Hypoplasia photograph (a D MIDD ratio of greater than 3 Optic nerve hypoplasia is a unilateral or bilat­ is considered diagnostic). Another method is eral, non-progressive condition which results by measuring the horizontal diameter of the from an excessive loss of axons of the involved optic disc from a 35 mm transparency; optic optic nerve before its full development. 1.2 discs less than 3.4 mm in horizontal disc diam­ It is characterised by the presence of a small eter can be considered hypoplastic in subjects optic disc often surrounded by an inner yellow with no major ametropia.I'] Although not ring and an outer pigmented ring, which com­ diagnostic the pattern and flash visual evoked prises the 'double ring sign' (Fig. 1).4 The potential may also be of assistance in that it major blood vessels coming off the hypoplas­ may help to identify and quantify the postreti­ tic optic disc are usually normal although nal defect in which the responses are atten­ sometimes they may be tortuous. 2 Only a part uated; the electroretinogram is normal. of the disc may be hypoplastic. Superior seg- The cause of optic nerve hypoplasia is

From the Hospital for Sick Children and The Institute of Child Health, London.

Correspondence to: Mr D. S. 1. Taylor. FRCS. FRCP. FCOphth. Hospital for Sick Children. Great Ormond Street, London WCI. THF SYSTF\lIC A�() (iF"EI IC SI(i�II'ICANCF en CODA 471

De Morsier's syndrome (septo-optic dys­ plasia) is recognised by the clinical triad of short stature, and optic disc hypo­ plasia.I" It is characterised by a spectrum of midline developmental anomalies associated with optic nerve hypoplasia and possible hypopituitarism."I?I" These midline develop­ mental anomalies may involve the optic chiasm, optic tracts. the septum pellucidum. corpus callosum, 3rd ventricle. hypothalmus, pituitary stalk, and the pituitary gland."17-1" Other central nervous system abnormalities associated with this syndrome include cere­ bral and cerebellar atrophy. hydrocephalis. cerebral infarcts. and porencephalic cystS.'I"'" About two-thirds of patients with De Morsier's syndrome are estimated to have some form of pituitary hypofunction.'I" The pituitary hypofunction varies from a defi­ ciency of growth hormone to panhypopituita­ rism." The most common pituitary Fig, I. 0l!lic disc In'f'ofJlllsili. rll" OilIer rillg of III" abnormality is that of growth hormone defi­ dOllbl" rillg is IIbolll [II" si:" of ({ ,wrIIl

. strabismus. nystagmus and posterior lenticonus.2.25.26 When associated with systemic problems they can be divided into four groups." (1) Neurological aSSOCJatlOns: Dandy Walker cyst. arhinencephaly. anencephaly. agenesis of the corpus callosum. and sphenoi­ dal encephalocoeles. The morning glory disc anomaly (see below) may also be associated with some of the above neurological associations. .17 (2) Chromosomal abnormalities: trisomy 13-15. 18. 22; cat eye syndrome; 4p- syn­ drome and monosomy 9. 1Ip-. 13q- and trip­ loidy. Many of these syndromes are not compatible with life. The ocular anomalies of trisomy 13-15 (Patau's syndrome) may include microphthal­ mia. retinal dysplasia. optic nerve hypoplasia.

persistent hyperplastic primary vitr@om. Cdt. aract, anterior cleavage syndrome. corneal opacities. cyclopia. intraocular cartilage and colobomas of the optic nerve. iris. and/or pos­ terior pole.27"� Other abnormalities include those of the heart and palate."� Fig. 2. Optic disc coloboma. The optic disc is Trisomy 18 (Edward's syndrome) may have enlarged with an excavaled centre. This p{{(ient had any of the following ocular characteristics assoiated renal and anal abnormalities. present: microphthalmia. prominent epican­ optic disc colobomas) and optic nerve thic folds. . . hyper­ colobomas.2 telorism. optic disc anomalies. uveal Optic nerve colobomas are usually unilat­ colobomas. congenital . and corneal eral although bilateral colobomas are quite opacitiesY Affected infants are feeble with frequent but asymmetrical. 25 Most are spor­ characteristic facies. mental retardation and adic although an autosomal dominant heredi­ cardiac abnormalities. 2� tary pattern has been reported and less (3) Syndromes: Meckel-Gruber syndrome frequently autosomal recessive or X-linked (autosomal recessive). Goltz syndrome (X. recessive pedigrees.25 Chromosomal analysis should be considered in children with optic disc colobomas. Optic disc colobomas may appear as large excavations of the nerve head up to 25 dioptres deep and involving nearly all of the disc which may be enlarged (Fig. 2).25 The colobomas may assume different forms including optic disc pits. peripapillary staphy­ lomas. and a variety of anomalous dysplastic forms.16 If the macula or optic nerve is involved then there may be a reduction in visual acuity.2 Optic disc colobomas may be associated Fig. 3. Aicardi"s syndrome. The right eye with a variety of ocular anomalies including demonstrates peripapillary hypopigmellted lacunae. posterior embryotoxon. nonrhegmatogenous 771(' eye was also microphthalmic. THE SYSTEMIC AND GENETIC SIGNIFICANCE OF CODA 473

terised by an enlarged and often excavated optic disc with a central core of white glial tis­ sue and surrounded by a pigmented raised annulus of subretinal tissue (Fig. 5);37 how­ ever. it may have slightly varying configura­ tions. ,7 The majority of the cases are unilateral. 37 Visual acuity is generally poor (6/36 to light perception) but rarely may be good.'� Patients usually present with strabismus or poor vision in one eye.'17 Up to one-third of cases develop serous retinal detachment. 33 It may be associated with a host of other ocular Fig. 4. Aicardi's sl'lIdrome. The leJi fTC or the same anomalies including . strabismus. patient as ill Figure 4. The lacullae are less ohvious hLit foveal hypoplasia. preretinal gliosis. pupillary are preselll helow the optic disc. The ere was of IlOrlllal size. membrane remnants and aniridia to name a few."7 Systemic abnormalities that it may be linked dominant) and the Lenz Microphthal­ associated with include basal encephalocoele. mia X-linked recessive) s ndrome. ( y absent corpus callosum. cleft lip and palate. The Meckel-Gt'uber �yndrorne k an auto· and reonl nbnMf11alitii:!� but man (1!1Stls Od(1Uf somal recessive condition characterised by in isolation.17 Excavation results from a mes­ coloboma. microphthalmos. cleft palate. enchymal defect.'· Either there is faulty micrognathia. polydactyly. renal abnonnali­ closure of the posterior scleral wall and lam­ ties, encephalocoele and cryptorchidism.'''' ina cribrosa with subsequent herniation of ret- The Goltz syndrome is an X-linked domi­ nant condition characterised by colobomas. focal dermal hypoplasia. and variable mental retardation. 'I The Lenz Microphthalmia syndrome is an X-linked recessive condition characterised by colobomas. prominent ears. skeletal defects. and crowded teeth. 32 (4) CHARGE association. The CHARGE association includes patients with at least four features prefixedby the letters of the CHARGE mnemonic: Colo­ boma. Heart defects. Atresia of the choanae. Retarded growth and development. Genital hypoplasia. Ear abnormalities andlor hearing loss.26 Facial palsy. renal abnormalities. tra­ cheo-oesophageal fistulae. and orofacial clefts may also accompany the above main features. 2(, Russell-Eggitt et al. found that 86% of patients with the CHARGE associ­ ation had ocular abnormalities.26 They reported that the majority had retinochoroi­ dal colobomata with optic nerve involvement. Some of the changes were subtle with some­ times only pallor of the retinal pigment epi­ thelium inferonasal to the optic disc.ch Fig. 5. The Moming Clary Disc Anonlaly. This is an The Morning Glory Anomaly enlarged optic disc with raised peripapillary tissue and The morning glory disc anomaly is charac- glial tisslle ill the centre oflhe concavity ofthe optic disc. 474 M. JACOBS A�D D. TAYLOR inal and neural tissue, or perhaps there is a young children. j Pcd Ophthalmol Strai> 1988.25 closure defect of the embryonic fissue.3.).37 (3): 151--4. 'Novakovic P. Taylor D. Hoyt W: Localising patterns of optic nerve hypoplasia- to Occipital AicardPs syndrome lobe. Br.l Ophthalmol 198H. 72: 176--9. This syndrome is characterised by infantile 4 Benner J. Preslan M. Gratz E. Joslvn J. Schwartz M. ( spasms, absence of the corpus callosum and Kelman S: Septo-optic dysplas a in two siblings. Am j Ophthalmol 1990. 109: 632-7. III defects in the .30 It is nonfamilial and Roberts-Harry J. Green S. Wilshaw H: Optic nerve occurs in persons with two X chromosomes. hypoplasia: associations and management. Arch Dis Childhood 1990. 65: 103-6. The choroidal lacunae are usually bilat­ II eral.l< Clinically they are well defined hypo­ Hovt CS and Bil l son F: Maternal anticonvulsants �nd optic nerve hypoplasia. Br .I Ophthalmol pigmented lesions with minimal surrounding 1978.62: 3-6. pigment, and tend to occur around the optic " Robinson CG and Conrav RF: Maternal age and disc (Figs 3 and 4). They appear to be a defect congenital optic nerve hypoplasia: a possil;le cl ue to aetiology. Child NCllrol I YH6. 28:294-8. in the retinal pigment epithelium and choroid · "Miller M. Is�· ael J. Cuttone J: Fetal Al cohol Syn­ without significant retinal involvement. 3< drome. .I Ped Ol'ht!l{/ImolStrahis 1984.55: 595-8. Adjacent to the disc there may be an elevated " Hoyt CS: Optic disc anomalies and matcrnal inges­ glial anomaly with grey pigmentation.30 tion of LSD. .1 Ped Opht!wllllol Strabis 1978. IS: 2H6-9. In three of four cases described by Hoyt et I' Taylor 0: Congenital tumours of the anterior visual al. associated optic nerve colobomas were �ystem with �lvspl;l'ia of the optic discs. Br J Oph­ present.30 Other ocular features which may be t!Uillllol I YH2. 66: 455-63. present include microphthalmos, persistent I" Gl aser J: Topical diagnosis: Prechiasmal visual path­ pupillary membranes, and glial tissue extend­ way,. Duane's Clinical Ophthalmology. JB Lip­ pincott Co. Revised Edition IYH9. Vol 2: Chp 5. ing from the optic disc.'o , - De Morsier G: Median cranioencephalic dysraphias World Neuro11962. The seizures usually occur within the first and olfactogenital. dysplasia. two months of life; they may occur as infantile 3: 4iS5. spasms or seizures of a more generalised dis­ "Kaufman L. Miller M. Make M: Magnetic reson­ ance imaging of pituitary stal k hyp(;pl asia. Arch order.41 The infantile spasms occur in flexion OphthlllmollY8Y. 107: 14HS-Y. but may also occur in extension.30 '" Margalith D . .fun TlC W. Jan J: Congcnital optic Other than agenesis of the corpus callosum, nervc hypoplasia with hypothal amic-pituitary vertebral anomalies (fusion of the vertebral dysplasia. Am.! [)is Child 19H5. 139: 361-6. ,,, Kaplan S. Grumbach M. Hoyt W: A syndrome of bodies), rib and hand anomalies, cortical het­ hvpopituitary dwarfism. hypoplasia of optic erotopia, hypotonia, microcephalia and men­ nerves and malformation of prosencephalon. tal retardation may be present.3 Y")O P"dilltr Res 1 Y70. 4: 4HO-I. " Hoyt W. Kaplan J. Grumbach M. Glaser J: Septo­ Key words: Coloboma. optic nervc hypoplasia. optic dysplasia and pituitary dwarfism. Lancet IY70. I: 893--4. "Costin G and Murphee A: Hypothal mic-pituitary References function in children with optic nerve hypopl asia. I Lambert SR. Hoyt CS. 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changing perspectives. AlIstr NZ j Ophthalmol 'I> Russel l -Eggitt I. Bl ake K. Tavlor D. Wvse- R: The 1986. 14: 325-3 \. eye in tl�c CHARGE asso�iation. Rr j Ophthal­ (, Romano PE: Simpl e photogammetric diagnosis of l11011Y90. 74: 421-6. optic nerve hypoplasia. Arch Ophthalmol 19H9. "Mets M: The eve and the chromosome. Duane's 107: H24--26. Clinical Opl� thalmology. JB Lippincott Co. - Al varez E. Wakakura M. Kahn Z. Dutton G: The Revised Edition 19K9. Vol 5: Chp35. disc-macul a distance (0 disc diameter ratio: a new "Hoepner J and Yanoff M: Ocular anomalies in tri­ (est for confirming optic nerve hypoplasia in somy 13-15. Am j OphthalmoI1972. 74: 729-37. THE SYSTEMIC AND GENETIC SIGNIFICANCE OF CODA 475

"Mullaney J: Ocular malformations in trisomv 18 ;" Kim R, Hoyt W, Lessell S, Narahara M: Superior (Edward's syndrome). Am J Ophthalmol t973, segmental optic hypoplasia. A sign of maternal 76: 246-54. diahetes. Arch Ophthalmo/19k9, 107: 1312-15. )11 Opitz J and Hov.e J: The Meckel Syndrome. Birth Trahoulsi M and O'Neill J: The spectrum in the mor­ Delects 1969,5: 167-79. phology of the so-called "Morning Glory Disc )1 Warhurg M: Focal Dermal Hypoplasia: ocular and Anomaly". J Ped Ophthalmol Strabis 1988, 25 general manifestations with a literature survey. (2): 92-k. Acta Ophthalmol (Khh) 1970,48: 525-36. " Hamada S, Inoue Y. Matsuda K: A case of morning )' Baraitser M, Winter R, Taylor D: The Lenz Microp­ glory syndrome with good visual acuity. Jpn J hthalmia Syndrome. C/ill Generics 19iQ, 22: OphtiIlIlmoI197k,32: 196-7. - 99-101. ;" Dennis J and Bower B: The Aicardi svndrome. Del' )) Haik B, Greenstein S. Smith M: Retinal detachment Med Child NellroI197(), 14: 382-9 0 . in the morning glory anomaly. Oplllllillmolof!,Y "" De Jong J, Delleman J, Houhen M: Agenesis of the 1984,91: I63k-47. corpus callosum, infantile spasms, ocular anoma­ "Dempster A, Lcc W, Forrcster J, McCreath G: The lies (Aicardi's syndrome). Neurology 1976, 26: "morning glory syndromc"-A mesodermal 1152-8. defect" Ophtlwlmolof!,ica19 83 , 187: 222-30. "' Aieardi J, Lefebvre J, Lerique-Locchlin A: A new 35 Hoyt C. Billson F. Ouvrier R. Wise G: Ocular fea­ syndrome: Spasm in flexion, callosal agenesis, tures of Aicardi's sYndrome. Arch Ophthalmol ocular ahnormalities. Electroencephalof!,r Ciin 197k, 96: 291-5. - Neurophysioll965, 19: 609 -1 0 .