66467 Med Genet 1993; 30: 664-669 Classification of microphthalmos and J Med Genet: first published as 10.1136/jmg.30.8.664 on 1 August 1993. Downloaded from

Mette Warburg

Abstract Phenotypic classification A new classification of microphthalmos A structured assessment of congenital defects and coloboma is proposed to bring order is necessary in the clinical delineation of syn- to the complexity of clinical and aetio- dromes and associations. A phenotypic classi- logical heterogeneity of these conditions. fication is helpful in systematic recording of A phenotypic classification is presented all pathological manifestations; the anomalies which may help the clinician to give a observed may also suggest the initial embryo- systematic description of the anomalies. logical error, or the time during pregnancy The phenotype does not predict the aetio- when development took an abnormal course. logy but a systematic description of ocu- lar and systemic anomalies improves syndrome identification. There are two MICROCORNEA total and The mean horizontal diameter of the neonatal major classes, partial microph- is 98 mm,4 with a range of 9 0 to thalmos, and a subclassification which 10 5 mm. The average vertical diameter of the follows the embryology of the anomalies. adult cornea is 10 6 mm, and the horizontal is The aetiological classification consists 11 75 mm.3 The true diameter of the cornea is of three classes: (1) genetic (monogenic difficult to measure if the limbus is indistinct and chromosomal), (2) prenatally acquired and in these cases transillumination of the (teratological agents and intrauterine will show the ciliary ring. deformations), and (3) associations. Gen- Microcornea may occur as an isolated anom- etic disorders give rise to malformations; aly or associated with other ocular disorders; in prenatally acquired anomalies are dis- each case it may be associated with systemic ruptions or deformations. anomalies. Microcornea without foreshor- The aetiological classification can be tened axial length has been described in the applied to other congenital birth defects oculodentodigital syndrome,5 but microcornea and improves counselling of families. usually appears in eyes in which both the Recurrence risks vary considerably anterior and posterior axial lengths are short.6 between the classes. It may also happen that patients have micro-

(J Med Genet 1993;30:664-9) cornea associated with ,7 or other http://jmg.bmj.com/ anterior segment malformations, and a normal sized posterior segment; further, microcornea Microphthalmos and coloboma are common can be present with posterior macrophthal- malformations. Microphthalmos is found in mos.8 Axial length measurements by ultraso- between 1-2 and 1-8 per 10 000 births in white nographic A scans are therefore advisable in populations and colobomata in 0-7 per 10 000 patients with microcornea. If there are anterior births.' 2 chamber malformations, glaucoma is a risk. In Anophthalmos is extreme microphthalmos microcornea, the corneal power is increased, on September 25, 2021 by guest. Protected copyright. and clinical conditions with anophthalmos are probably because of a small radius of curva- therefore equivalent to conditions with mic- ture. In severe microcornea, however, Weiss et rophthalmos.3 Congenital cystic eye is a mal- al8 found a decrease in corneal power because formation resulting from a failure of invagina- in very small corneae the curvature of the tion of the optic vesicle, and should therefore cornea approximates that of the . be classified with cases of microphthalmos. Colobomata of the uvea are often associated with microphthalmos and a classification of MICROPHTHALMOS microphthalmos should therefore also include The size of the globe can be measured ultra- tomo- coloboma. Microphthalmic eyes usually have sonographically, by computerised graphic scans (CT scans), or by magnetic reso- microcornea, so microcornea should be in- nance imaging (MRI). Fetal ultrasonograms of cluded in a discussion of microphthalmos. the eye can be obtained both transabdomi- The eye derives from three embryological nally9 and by a transvaginal procedure in the germ layers: the neuroectoderm which gives transverse section.10 Normal values for fetal rise to the optic vesicle, the neural crest cells axial length" and for the growth of the fetal Division of Paediatric which migrate to the anterior chamber of the orbit9 are available; in hereditary cases, mic- Ophthalmology and developing eye, and the ectoderm from which Handicaps, Gentofte rophthalmos may be diagnosed prenatally by Hospital, 40 Sognevej, the placode is derived. Neuroectodermal expert ultrasonography.'0 The length of the DK-2820 Gentofte, and mesodermal cells participate in the closure neonatal eye is presented in table 1.4 There is a Denmark. of the fissure.3 This M Warburg optic multiple embryologi- close correlation between the weight of the cal derivation explains the variability of the neonate and its axial eye length. Received 24 October 1992. the Revised version accepted phenotype and aetiological heterogeneity The growth of the eye is fast during the first 8 March 1993. of congenital ocular defects. three years'8; the adult size is reached at Classification of microphthalmos and coloboma 665

Table 1 Axial length of the neonatal eye (modifiedfrom Blomdahl3). mos. In these cases the eyes are usually deeply Larsen"l'4 Gemet" Luycks'6 Grignolo Blomdahl' set in the orbit, refraction is high hypermetro- and Rivara'7 pic, and the cornea is small. Both the anterior J Med Genet: first published as 10.1136/jmg.30.8.664 on 1 August 1993. Downloaded from Anterior chamber 2 4 2-9 2 6 - 2 6 and posterior segments of the eye are foreshor- Lens 3.9 3.4 37 - 36 tened, the relative lens volume is Vitreous 10 4 - 10-8 - 10-4 increased, Total axial length - 17 2 17 6 17-0 16 6 and there is sclerochoroidal thickening.2324 No of eyes 90 70 104 36 28 (D) Microphthalmos with other ocular malfor- mations is common. (1) Microphthalmos with congenital cataract is known in both rodents25 around 13 years, when the outer sagittal dia- and man, for example, in the sporadic Haller- meter is 24 mm, the inner sagittal 22 mm, the mann-Streiff syndrome,26 and the X linked anteroposterior 25 mm, and the transverse Nance-Horan syndrome.27 (2) The chamber 24 mm.3 19 angle may be deficiently developed and there Microphthalmos is assessed when the axial may be anterior synechiae. This has been seen diameter, adjusted for age, is below the 95th in rodents treated with teratogens28 and in centile. In adults, microphthalmos is identified human families, for example, in an Indian in eyes with an axial length of less than sibship with microphthalmos, sclerocornea, 185 mm.1'9 The phenotype of patients with anterior chamber 'dysgenesis', and congenital microphthalmos and coloboma is highly vari- cataract.29 There may be defects of the poster- able, but can be classified as shown in tables 2 ior layers of the cornea and the cornea may be and 3. cloudy. This has been observed, for example, I. Total microphthalmos is where both in a sister and brother with microphthalmos, anterior and posterior segments are foreshor- microcornea, and sclerocornea associated with tened. The most serious type of microphthal- fine sparse hair, a narrow nasal bridge, pro- mos is (A) congenital cystic eye which is the truding, cupped ears, and a short upper lip.30 condition that follows if the optic vesicle fails (3) Colobomata of the uvea (a) are often pres- to invaginate. In these cases there is no trace of ent in microphthalmic eyes. They may be of the globe2021; the cyst has a tendency to in- varying size and may involve or spare the ; crease in size and should be removed at an minor manifestations can be seen by transillu- early age in order to place a conformer which mination. There may only be a small notch in may expand the orbit.22 the pupil signalling a very small coloboma. A (B) Anophthalmos is the clinical term for retinochoroidal coloboma may be so small that extreme microphthalmos where ocular struc- only a small change in the colour of the retinal tures can be found only by serial histopatho- pigment epithelium discloses its presence, or, logical sections. in contrast, it may involve all the structures (C) Simple microphthalmos without other between the optic nerve and the ciliary body. major malformations is termed nanophthal- The macula is often involved. The optic nerve

may be part of a coloboma (b) of the posterior http://jmg.bmj.com/ Table 2 Phenotypic classification of microphthalmos. pole. The colobomatous part may become staphy- I Total microphthalmos (A) Congenital cystic eye lomatous and sometimes the coloboma forms a (B) Apparent anophthalmos cystic lesion in microphthalmic eyes (c). This (C) Simple microphthalmos (D) Microphthalmos with intraocular malformations cyst may press the eye forwards in the orbit in (1) Congenital cataract which case it is difficult to assess that the eye is, (2) Anterior chamber malformations (3) Coloboma in fact, too small; CT scans are useful for this on September 25, 2021 by guest. Protected copyright. (a) Coloboma of the uvea evaluation.3132 (b) Coloboma of the optic nerve (c) Cystic coloboma (E) Microphthalmos with multiple ocular mal- (E) Multiple ocular malformations formations, that is, malformations deriving II Partial microphthalmos (A) Anterior segment microphthalmos from different embryological germ layers are (B) Posterior segment microphthalmos also found; examples are Delleman syndrome (the oculocerebrocutaneous syndrome),33 and the osteoporosis-pseudoglioma syndrome.34 Table 3 Phenotypic classification of coloboma. II. In partial microphthalmos, the anterior I Typical chamber and the cornea may be of normal size (A) Coloboma of the iris even if the posterior segment is small.35 Poster- (a) Complete (keyhole) (b) Partial ior segment microphthalmos is seen, for in- (1) Peripheral stance, in patients with high hypermetro- (2) Notch in the pupil (3) Pigment epithelium defect pia.'836 In some patients the anterior chamber (4) Heterochromia of the iris is small while the posterior compartment is of (B) Coloboma of the ciliary body (C) Coloboma of the choroid normal size37 or larger than normal.38 (1) (a) Partial (b) Complete Coloboma means mutilation; it indicates that (2) (a) With (b) Without macular involvement (3) (a) Cystic (b) Non-cystic a portion of the eye is lacking. Colobomata of (D) Coloboma of the optic nerve the posterior segment of the uvea of both adult (1) Typical (a) Cystic (b) Non-cystic and fetal eyes can be visualised with ultrasono- (2) Special graphy, MRI, or CT scan even if the optic (a) Pits of the optic nerve (b) Pedler coloboma media are cloudy.3"' (c) Morning glory The term 'coloboma' is used for three types (d) Optic disc hypoplasia II Atypical of malformations, typical, atypical, and mac- Coloboma outside the optic fissure ular. Typical colobomata are situated infero- I I I Macular 'coloboma' nasally at the site of the optic fissure, whereas 666 Warburg

atypical colobomata may be situated at any cyst.4' The embryological pathology of pits, other site. The development of the latter is not Pedler coloboma, and morning glory malfor- related to closure of the optic mations have not been definitively explained. clear, but it is not J Med Genet: first published as 10.1136/jmg.30.8.664 on 1 August 1993. Downloaded from fissure. Macular 'coloboma' is the name given Some authors believe that pits, Pedler col- to a heterogeneous group of anomalies charac- oboma, and morning glory optic nerves are terised by a pigmented malformation in the defects of closure of the optic fissure.3434753 macula. They are not embryological coloboma. However, Mann54 and Brown et al55 were Only typical coloboma will be discussed (table undecided as to the pathogenesis, and Man- 3). chot,56 on the basis of a histopathological ex- Most previous classifications of colobomata amination of a case of the morning glory syn- have been aetiological,4243 but there are surveys drome, proposed that it was a mesodermal of coloboma in which the classification is lesion and not a coloboma. The embryology of partly phenotypic and partly aetiological.44 optic nerve hypoplasia is undoubtedly hetero- Since the phenotype does not predict the aetio- geneous. logy, it is more logical to keep the two types of classification apart, as in the survey of Pagon.45 Colobomata appear as coloboma of the iris, Aetiological classification the lens, the ciliary body, the choroid, the optic The correlation between phenotype and aetio- nerve, or as staphylomatous colobomata or logy is poor in most congenital defects and also microphthalmos with cyst, or in combinations where microphthalmos is concerned. The cli- (table 3). Special cases of coloboma comprise nician, therefore, needs a structured approach pits of the optic disc, Pedler coloboma, the to the identification of an aetiology and this is morning glory malformation, and optic nerve where a classification is helpful. An aetiological hypoplasia. classification of microphthalmos is shown in Pits are non-hereditary crater-like depres- fig 1. There are three classes: (1) genetic sions of the nerve head, first described by (monogenic and chromosomal), (2) prenatally Wiethe46; the majority of them are situated at acquired (teratogenic disruptive causes and the temporal side of the disc. In contrast to deformations), and (3) associations. typical colobomata, pits are not associated with systemic malformations. Pits have, however, been described in colobomatous eyes.479 GENETIC DISORDERS In Pedler coloboma50 the scleral canal is There are more than 100 genetic traits with abnormally wide and filled with loose connec- microphthalmos and coloboma. There are ap- tive tissue. There is an epipapillary mass con- proximately 50 different autosomal dominant sisting of buckling of the overlying retina syndromes, 67 autosomal recessive syndromes which gives the impression of a tumour.35' with these malformations are known at pres- Muscle fibres are present in the wall and the ent, and there are 16 X linked syndromes with with disc can be seen pulsating synchronously microphthalmos and coloboma.57 Mitochon- http://jmg.bmj.com/ respiration.445152 drial mutations or deletions have not, so far, The morning glory malformation is also an been described as a cause of microphthalmos. excessive deepening of the optic nervehead. A The disorders which arise from genetic anom- tuft of glial and vascular tissue projects into the alies are termed malformations.2658 In some vitreous, and the retinal vessels are seen at the disorders ocular malformations are isolated margin of the depression. Optic nerve hypo- signs, for instance, autosomal dominant colo- plasia is considered by some to represent a type boma-microphthalmos,59 but it is much more of coloboma because it has occasionally been common that systemic features are part of the on September 25, 2021 by guest. Protected copyright. described in patients in whom the other eye symptomatology. The associated features may had a coloboma43 or microphthalmos with involve the brain, as in holoprosencephaly,60 skin, as in focal dermal hypoplasia,6' internal Aetiology of microphthalmos organs, as in Meckel's disease,62 or the extrem- ities, as in the oculodentodigital syndrome.5 The importance of chromosomal disorders in ophthalmology was realised very early.6364 Genetic Prenatally Unknown acquired Deletions and translocations of almost all chromosomes may present with microphthal- mos or coloboma.65 The most common ones Malformations and syndromes Associations are trisomies 13 and 18, del(l8p), del(I 3q), and del(4p),66 but microphthalmos or coloboma in mentally handicapped patients with two minor malformations should always raise the suspi- cion of a chromosomal aberration.

Deletions Medication Rubella ADAM CHARGE Duplications i abuse Diabetes Encephalo- VATER Polyploidy Poisoning Toxoplas- cele PRENATALLY ACQUIRED MICROPHTHALMOS AND Transloca- Irradiation mosis Tumours COLOBOMA tions CMV The term prenatally acquired indicates that the embryo or fetus had a normal genetic Figure 1 Aetiological classification of microphthalmos. The three major classes, background but that the intrauterine environ- genetic, prenatally acquired, and unknown aetiology, are subdivided into or deforma- malformations and syndromes, disruptions, deformations, and associations. The final ment resulted in disruptions classes consist of identified disorders. tion.26 58 Disruptive microphthalmos has been Classification of microphthalmos and coloboma 667

described as a consequence of maternal inges- cases. These anomalies are often, but not al- tion of teratogens, among them alcohol,67 thali- ways, present in the CHARGE association and domide,68 69 and isoretinoic acid.70 Maternal may be seen in the VATER association.75 diabetes and maternal rubella are the best J Med Genet: first published as 10.1136/jmg.30.8.664 on 1 August 1993. Downloaded from known diseases which may delay the normal growth of the eye.7' In a singular case, it was Discussion postulated that during amniocentesis the The object of a phenotypic classification is to needle had perforated the eye of a fetus.72 identify clinical syndromes or associations. Deformations of the fetal eye have been The phenotypic classification of microphthal- observed in cases with microphthalmos where mos and coloboma predicts neither the geno- a large choristoma compressed the developing type nor an agent which may have caused the eye,7374 and in patients who had an encephalo- malformations. In bygone years, microphthal- cele which compressed the orbit.75 Oblique mos was classified into 'pure', 'colobomatous', facial clefts are supposed to derive from the and 'complicated' microphthalmos.'982 The swallowing of amniotic bands. When a band first two classes referred to the ocular morpho- traverses the fetal eye, microphthalmos or even logy; in contrast, the third referred to the clinical anophthalmos may occur.7677 Colobo- presence of systemic anomalies and not to mata have also been described in eyes in which specific ocular features. The phenotypic classi- choristomas or mesodermal tissue were pres- fication presented here is concerned with the ent in the line of closure of the optic fissure,44 ocular features only. The phenotypic classes but it is impossible to know if the coloboma are not nosological entities, but the phenotype preceded the abnormal tissue or was caused by of the ocular malformations together with the it. systemic signs may often lead to the identifica- tion of a recognised syndrome. The phenotypic classification does not at- ASSOCIATIONS tempt to split anophthalmos, congenital cystic Associations are non-random concurrences of eye, microphthalmos, and coloboma into dif- several particular, but variable, minor malfor- ferent aetiological classes. These congenital mations which are not pathogenetically anomalies may have the same aetiology in some related, or which are not known to have the cases, as seen, for example, in fig 2,83 where same principal aetiology.26 Lubinsky75 thought they all appeared in a single family. In con- that they were "derivatives of causally non- trast, there are more than 150 different causes specific disruptive events acting on develop- ofmicrophthalmos and coloboma. This under- mental fields". In other words, associations lines the necessity of an aetiological classifica- may be the result of teratogens which act at a tion. certain time on a certain area in a person who The aetiological classification gives a sys- responds in a certain way. Associations, there- tematic approach to the possible causes of the fore, would represent embryological relation- congenital anomalies. It makes distinctions http://jmg.bmj.com/ ships and timing, not specific causes. between malformations, disruptions, and Microphthalmos and coloboma resulting deformations. The clinician will often be able from associations represent only a minority of to differentiate between these, although there are sometimes overlaps. The embryology of Autosomal recessive the eye is so well known that anomalies can anophthalmos-microphthalmos-coloboma syndrome usually be delineated into those which are caused by genetic factors changing embryol- ogical growth and differentiation (malforma- on September 25, 2021 by guest. Protected copyright. tions), and environmental factors which do not comply with embryological barriers (disrup- tions and deformations). The present aetiological classification is not restricted to microphthalmos and coloboma, but is of general application in syndromology. Almost all congenital anomalies can be system- atically delineated into genetic (monogenic, mitochondrial, chromosomal) or prenatally acquired disorders. Recurrence risks obviously vary considerably between the classes. This work was supported by grants from 'The Eye Foundation', The Danish Association of the Blind, and the Velux Foundation.

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