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7.4.1 Patients

With 40 boys and 35 girls, the male–female distribution of the patient sample in this study showed a slight over- representation of males, somewhat in excess of the normal boy-to-girl ratio (approximately 108:100) in newborns. Unilateral anophthalmos (38 patients) was present almost twice as commonly as bilateral anophthalmos (20 patients). With a single exception, the 17 patients with microphthal- mos all showed unilateral pathology.

Th ere are only a small number of publications dealing systematically with investigations in a comparably large group of patients with congenital anophthalmos. Th e defi nitive article published by Collin’s group [23] studied a comparable population in terms of patient numbers, gender, and sample breakdown. However, that study included almost twice as many microphthalmos patients as anophthalmos patients, and this is a marked departure from the population described here, in which 3.4 times as many anophthalmos as microphthalmos patients were

treated. It is likely that patients with microphthalmos were managed better elsewhere with conformers or pros- theses than those with clinical anophthalmos and there- fore were not referred to us in Rostock for expander therapy; this theory would explain their marked relative underrepresentation.

It is noteworthy that in unilateral disease anophthal- mos was encountered about 50% more oft en on the right side (n = 32) than on the left (n = 22). In microphthalmos, the right-to-left ratio was balanced (n = 8:8). Th ere is no known—or published—explanation for this.

7.4.2 Obstetric and Family History

Th e obstetric course was unremarkable for all children. Th ere was no direct relationship between obstetric his- tory and anophthalmos/microphthalmos. A history of abnormalities during pregnancy was reported for 11 of the 75 mothers. It has been suggested that the factors most likely to be implicated in the etiology are maternal

all patients normal UCB BCB CCB CNLDO Anophthalmos Microphthalmos

Fig. 7.5 Nasolacrimal duct fi ndings in anophthalmos and microphthalmos. UCB unicanalicular block, BCB bicanalicular block,

CCB common canalicular block, CNLDO congenital nasolacrimal duct obstruction

Summary for the Clinician

Male–female distribution is almost balanced. It ■

is not known why anophthalmos involves the right eye 1.5 times more oft en than the left eye.

vitamin A defi ciency, exposure to X-rays, and gestational- acquired 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 microphthal- mos. In our own patients, consanguinity was established in only one child. Taken together with the described genetic fi ndings in the parents and the single case with a positive family history, however, this points to the puta- tive role of genetic factors. It seems clear that ano- phthalmos and microphthalmos have a complex and multifactorial etiology that includes chromosomal fac- tors, such as duplications, deletions, and translocations, as well as monogenic causes. Among the monogenic causes, SOX2 on chromosome 3 has been identifi ed 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]). Th e detailed workup for genetic diagnosis in our own patients is the subject of another ongoing study and is therefore not covered in this article.

7.4.3 Associated Pathologies

7.4.3.1 Ophthalmological Findings in Unilateral Disease

In 12 (75%) of the 16 patients with unilateral microphthal- mos, the fellow eye was morphologically and functionally normal; the condition was limited to a single eye. Th e 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 sclero- cornea, with the result that 13 children (34.2%) were cat- egorized as legally blind.

Th e distribution statistics are largely consistent with the details for 14 anophthalmos patients presented in the pre- viously cited study by Tucker et al. [23]. Th at publication provided no information on potential visual function.

In their group of 24 Indian children with anophthal- mos, Hornby et al. [9] did not fi nd 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 pres- ent 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 pub- lications 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.

7.4.3.2 Neuroradiological Findings

In technical terms, MRI is superior to computed tomog- raphy (CT) for the assessment of cerebral fi ndings [5, 7].

In our study sample, 15.9% of patients had fi ndings consistent with associated cerebral pathology. Th ese were encountered almost three times as oft en in bilateral ano- phthalmos (26.3%) as in unilateral anophthalmos (9.1%). Th e frequency of such fi ndings in unilateral microphthal- mos (12.5%) was comparable to that in unilateral

Summary for the Clinician

Consanguinity and pathological chromosome ■

fi ndings point to the involvement of genetic fac- tors, which are becoming an increasing focus of

research. 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 classifi ed as legally blind. Th erefore, the overall blindness rate was 17.6% in microphthalmos and 3.4 times higher (56.9%) in anophthalmos.

7

anophthalmos. Our study sample included only one patient with bilateral microphthalmos, and consequently no fur- ther diff erentiation was possible.

Th e most serious changes, detected in fi ve anophthal- mos patients, involved extreme hypoplasia—or complete agenesis—of the corpus callosum. Th is change aff ected 9.6% of the patients and was again far more common in bilateral (16.8%) than in unilateral (6.1%) disease. Septo- optic 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 develop- mental anomalies of the corpus callosum has been described in individual case reports [1, 5].

In view of the frequent occurrence of associated cere- bral developmental anomalies, it appears justifi able to recommend MRI examination for every child with these conditions.

7.4.3.3 Systemic 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 isola- tion. Th e 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 diff erentia- tion 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 fi g- ure 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%). Th ese published sta- tistics are consistent with our observations:

In our patient sample, 3 of 17 children with micro- phthalmos (17.6%) were found to have associated sys- temic 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 chil- dren aff ected (50%); most commonly, these were devel- opmental cerebral anomalies (n = 12), followed by (hemi-)facial anomalies (n = 9). Th e variable “unilateral versus bilateral” had no infl uence on absolute frequency. However, it is remarkable that the nature of the pathology is diff erent. Unilateral anophthalmos was associated most commonly with cleft ing (seven patients), which was not detected at all in the surgically managed patients with bilateral anophthalmos. (To date, bilateral cleft ing of lip, upper jaw, and palate has been noted just once in a child with bilateral anophthalmos who did not undergo sur- gery because of the underlying presence of trisomy 13; see Fig. 7.6.) In the children with bilateral anophthalmos, there was a defi nite predominance (7 of 10 aff ected chil- dren) of cerebral anomalies, which were encountered far less commonly (23%) in unilateral anophthalmos. It has been postulated that a general malformation of the fore- brain during embryological development might provide an explanation for the above-average incidence of the association between bilateral anophthalmos and devel- opmental anomalies of the optic chiasm and corpus cal- losum [1, 10]. Meanwhile unilateral anophthalmos arises mainly in association with developmental anomalies of the fi rst and second pharyngeal arches, such as Goldenhar syndrome. Th is 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].

7.4.3.4 Nasolacrimal Duct Findings

On the side aff ected by anophthalmos or microphthal- mos, 80% of patients presented with stenosis of the nasolacrimal duct system. Canalicular (62%) and presac- cal (11%) stenoses accounted for the largest proportion of

Summary for the Clinician

Th e frequent occurrence of developmental cere- ■

bral anomalies, particularly those involving the corpus callosum, warrants MRI examination for all children aff ected.

Summary for the Clinician

Associated systemic fi ndings were more numer- ■

ous and more severe in patients with anophthal- mos (50%) than in those with microphthalmos (17.6%).

these occlusions. Obstruction of the valve of Hasner, oth- erwise typical in this age group [12], played only a minor role in our patients even though the incidence of 8% was approximately consistent with the incidence for this age group, which is reported in the literature to be as high as 15% [14, 15, 17].

In 1887, Collins [4] supplemented the 30 anophthal- mos cases published in the literature up to that time with 12 new cases and pointed out the occasional absence of the lacrimal puncta and canaliculi. Th e lacrimal puncta were always present in our patients.

To date, there have been no comprehensive newer studies of the nasolacrimal duct system in anophthalmos. One case report has described an association between congenital stenosis of the valve of Hasner and congenital anophthalmos [16], but the results presented in our study suggest that this is rather the exception.

So far, the high incidence of nasolacrimal duct anom- alies has therapeutic implications only when there is clas- sic congenital stenosis of the valve of Hasner that is successfully corrected in the course of diagnostic prob- ing. Bearing in mind the possible presence of a pathogen reservoir, elimination of the obstruction should be per- formed so expander therapy is not jeopardized by infec- tion-related complications. However, the vast majority (91.3%) of all stenoses were diagnosed in presaccal loca- tions; because the development of infl ammation is not to be expected, surgical management is indicated here only in troublesome epiphora [20].