vitamin A deficiency, exposure to X-rays, and gestationalacquired infections [24]. In our own patients, for the majority of anomalies reported, there was no discernible link with the children’s anophthalmos/microphthalmos in terms of factors reported in the literature.

In an Indian population, Hornby et al. [9] reported a consanguinity rate of 64% in 24 children with microphthalmos. In our own patients, consanguinity was established in only one child. Taken together with the described genetic findings in the parents and the single case with a positive family history, however, this points to the putative role of genetic factors. It seems clear that anophthalmos and microphthalmos have a complex and multifactorial etiology that includes chromosomal factors, such as duplications, deletions, and translocations, as well as monogenic causes. Among the monogenic causes, SOX2 on chromosome 3 has been identified as a principal gene that is responsible for 10–20% of (mainly bilateral) anophthalmos [6]. Other linked genes include PAX6, OTX2, CHX10, FOXE3, and RAX (for comprehensive discussion, see [24]). The detailed workup for genetic diagnosis in our own patients is the subject of another ongoing study and is therefore not covered in this article.

Summary for the Clinician

■Consanguinity and pathological chromosome findings point to the involvement of genetic factors, which are becoming an increasing focus of research.

7.4.3Associated Pathologies

7.4.3.1Ophthalmological Findings in Unilateral Disease

In 12 (75%) of the 16 patients with unilateral microphthalmos, the fellow eye was morphologically and functionally normal; the condition was limited to a single eye. The remaining four children (25%) displayed pathological changes in the fellow eye, and in two of these cases (12.5%) the changes were so severe that the children were categorized as legally blind.

Twenty (70%) of 29 microphthalmos patients had a normal fellow eye in the study conducted by Tucker et al. [23]; the remainder displayed associated developmental anomalies of the fellow eye, although no information on visual acuity was provided.

In the present study, in 20 (52.6%) of the 38 patients with unilateral anophthalmos, the fellow eye was healthy

and had normal visual function. Eighteen children (47.4%) were found to have an associated developmental anomaly of the fellow eye, such as coloboma or sclerocornea, with the result that 13 children (34.2%) were categorized as legally blind.

The distribution statistics are largely consistent with the details for 14 anophthalmos patients presented in the previously cited study by Tucker et al. [23]. That publication provided no information on potential visual function.

In their group of 24 Indian children with anophthalmos, Hornby et al. [9] did not find any patients with a normal fellow eye. However, the children were recruited only from blind schools, a fact that explains the absence of children with one healthy or sighted eye and ultimately rules out any comparison with the population in the present study.

In summary, in terms of potential visual function, 46.7% of our study population were legally blind. When those children with obvious bilateral disease were left out of the calculation, the risk of blindness with presumed unilateral pathology was almost three times higher with anophthalmos than with microphthalmos. Previous publications have not referred to this aspect. It is therefore necessary to examine the fellow eye at an early stage to assess the potential development of visual acuity and, if appropriate, to initiate measures for its early promotion.

Summary for the Clinician

■On account of this pathology in a single eye, 2 (12.5%) of the patients with unilateral microphthalmos and 13 (34.2%) of the patients with unilateral anophthalmos, as well as all of the patients with bilateral anophthalmos, were classified as legally blind. Therefore, the overall blindness rate was 17.6% in microphthalmos and 3.4 times higher (56.9%) in anophthalmos.

7.4.3.2Neuroradiological Findings

In technical terms, MRI is superior to computed tomography (CT) for the assessment of cerebral findings [5, 7].

In our study sample, 15.9% of patients had findings consistent with associated cerebral pathology. These were encountered almost three times as often in bilateral anophthalmos (26.3%) as in unilateral anophthalmos (9.1%). The frequency of such findings in unilateral microphthalmos (12.5%) was comparable to that in unilateral

anophthalmos. Our study sample included only one patient with bilateral microphthalmos, and consequently no further differentiation was possible.

The most serious changes, detected in five anophthal-

7mos patients, involved extreme hypoplasia—or complete agenesis—of the corpus callosum. This change affected 9.6% of the patients and was again far more common in bilateral (16.8%) than in unilateral (6.1%) disease. Septooptic dysplasia was reported to be associated with an increased rate of sudden death in children [3]. Among our patients, one child with bilateral anophthalmos and corpus callosum aplasia died unexpectedly at the age of 16 months.

An association between anophthalmos and developmental anomalies of the corpus callosum has been described in individual case reports [1, 5].

In view of the frequent occurrence of associated cerebral developmental anomalies, it appears justifiable to recommend MRI examination for every child with these conditions.

Summary for the Clinician

■The frequent occurrence of developmental cerebral anomalies, particularly those involving the corpus callosum, warrants MRI examination for all children affected.

7.4.3.3Systemic Diseases

In their analysis of data from the Spanish Collaborative Study of Congenital Malformations in a series of 1,124,654 consecutive births, Bermejo and Martínez-Frías [2] noted 240 cases of anophthalmos (n = 47) or microphthalmos (n = 193). Only 9.6% of these defects occurred in isolation. The 90.4% occurring in conjunction with systemic diseases were subdivided into syndromes (32.9%) and multiple congenital anomalies (57.5%). Unfortunately, those authors did not undertake any further differentiation of concomitant systemic diseases to provide a basis for comparison.

A far lower rate of systemic disease associations (39%) was reported by Mouriaux et al. [13] in their study in 7 anophthalmos and 35 microphthalmos patients; this figure is comparable to the 37.7% incidence calculated by Tucker et al. [23], who noted associated systemic diseases in 7 of 34 microphthalmos patients (20.6%) and in 22 of 43 anophthalmos patients (51.2%). These published statistics are consistent with our observations:

In our patient sample, 3 of 17 children with microphthalmos (17.6%) were found to have associated systemic diseases, although the pathology tended to be of a less serious nature.

Associated systemic diseases were considerably more frequent in anophthalmos patients, with 29 of 58 children affected (50%); most commonly, these were developmental cerebral anomalies (n = 12), followed by (hemi-)facial anomalies (n = 9). The variable “unilateral versus bilateral” had no influence on absolute frequency. However, it is remarkable that the nature of the pathology is different. Unilateral anophthalmos was associated most commonly with clefting (seven patients), which was not detected at all in the surgically managed patients with bilateral anophthalmos. (To date, bilateral clefting of lip, upper jaw, and palate has been noted just once in a child with bilateral anophthalmos who did not undergo surgery because of the underlying presence of trisomy 13; see Fig. 7.6.) In the children with bilateral anophthalmos, there was a definite predominance (7 of 10 affected children) of cerebral anomalies, which were encountered far less commonly (23%) in unilateral anophthalmos. It has been postulated that a general malformation of the forebrain during embryological development might provide an explanation for the above-average incidence of the association between bilateral anophthalmos and developmental anomalies of the optic chiasm and corpus callosum [1, 10]. Meanwhile unilateral anophthalmos arises mainly in association with developmental anomalies of the first and second pharyngeal arches, such as Goldenhar syndrome. This suggests that the normal development of the mesenchyma, from which, for example, the maxilla and mandible are formed, is associated with the correct shaping of the eye and orbit, and that anomalies in this development may lead to degenerative (consecutive) anophthalmos [1].

Summary for the Clinician

■Associated systemic findings were more numerous and more severe in patients with anophthalmos (50%) than in those with microphthalmos (17.6%).

7.4.3.4Nasolacrimal Duct Findings

On the side affected by anophthalmos or microphthalmos, 80% of patients presented with stenosis of the nasolacrimal duct system. Canalicular (62%) and presaccal (11%) stenoses accounted for the largest proportion of