Discussion
Ophthalmic manifestations in PL have unsatisfactory documentation in the past, either in small series or case reports. However, combined data offer an approximate prevalence of ocular abnormalities.
A summary of embryonic development is necessary to understand the genesis and pattern of systemic malformations and its relationship with ocular abnormalities. Head and face development occurs between 4 and 8 weeks of embryogenesis. The insult during this period results in a constellation of malformations. However, the causative factor is uncertain.14
The development in early embryo occurs via series of orderly induction. Embryonic induction is a process by which a group of cells called ‘organiser’ influence and differentiate the adjacent embryonic cells. This is a recurring phenomenon and an array of organisers are produced in an orderly progression, from a ‘primary organiser’ to secondary and tertiary organisers, and so on. 'Each order of organisation results in a particular development abnormality'. The interaction between the inducer and the tissue being induced is probably chemically mediated. The extent of interaction is limited by finite distance and critical exposure time within a field volume. The influence of organiser is mostly found at the centre of the field volume and least at its periphery. An overlap from the surrounding organisers at the field perimeters may result in small or otherwise malformed structure.
The notochordal process is the first and the most important organiser in the head of the embryo. It induces formation of neural tube and foregut, which act as secondary organisers. The neural tube is closed by 4 weeks of gestation and a primitive forebrain (prosencephalon) emerges at its rostral end. Neural crest-derived mesenchyme from the prosencephalic region forms the unpaired central frontonasal process. During weeks 5 and 6 of gestation, a series of cleavages in the prosencephalon induce the neuroepithelium placodes in pairs (optic, otic, olfactory in the same order). Similarly, the foregut organises the formation of the maxillary process from the first branchial arch. The primary defect of ventral induction during prosencephalon development results in the most profound anomalies, holoprosencephaly. In holoprosencephaly, various states of failure of differentiation occur, including improper placement of the interplacode area. As a result, the central proboscis and other severe anomalies such as cyclopia, midfacial clefts and severe hypotelorism develop.15
The olfactory placode is the primary organiser of a developing nose. At week 5 of gestation, the nasal groove is formed from the olfactory placode. It interacts with a frontonasal process to define the maxillary process, the medial nasal process and the lateral nasal process. During weeks 6–7, the maxillary process induces transformation of the nasal and oral cavity. The medial nasal prominences merge with each other across the midline and interact with growing maxillary processes to form the intermaxillary segment. The ventral end of the median nasal process extends into the mesenchyme of the roof of the mouth. This enlarged area is identified as globular process. The interaction between maxillary process, lateral nasal process and the intermaxillary segment ultimately forms the upper lip, the zygomas, the maxilla bilaterally, the philtrum and the nasal bridge by week 10. The primitive anterior nares, mouth and alveolus form when the maxillary process meets the globular process. For all obvious reasons, the maxillary process is key to the development of facial structures. The maxillary process regulates and gets regulated by the optic, otic and olfactory centres.15 Hence, any localised facial defect may harbour maxillary maldevelopment and vice versa.
During expansion of the medial nasal prominence, a fissure may develop, leading to two abnormal fragments of the prominence. The abnormal lateral fragment merges with the lateral nasal prominence and forms PL. The medial fragment, which merges with the unaffected side, is destined to another fate. This deviation results in a PL with abnormal nose and an additional hypoplastic maxillary prominence can have various associated abnormalities. Alternatively, an extra nasal placode when arranged in a vertically stacked manner on the affected side forms a PL with a normal nose. The lower placode contributes to formation of a normal nose, while the upper placode remains isolated and develops into a PL.14 16
Development of eye and palate gets affected when the inductive influence on their adjacent fields deviates. Eye development begins with optic placode formation from the neuroectoderm at week 3 of embryogenesis. Around week 5, auto-invagination in the optic vesicles creates a double-walled neuroectodermal optic cup. At the same time the optic vesicles interact with the surface ectoderm to form lens placode, which transforms into future lens. The connections of optic vesicle to the forebrain attenuate to form optic stalks with a groove on their inferior surfaces. This groove is referred to as optic or choroidal fissure and closes by week 8. Inadequate closure of the optic furrow results in coloboma of the iris, retina and disc.14 The interplay between the maxillary process and other developing mass shapes the extraocular structure. At week 7, the maxillary process and the lateral nasal process interact to form the lacrimal apparatus. The nasolacrimal duct forms when plugged epithelium recanalise at week 24. The mesenchyme along the optic vesicle and maxillary process contributes to the formation of medial aspect of the lower eyelid.
The line of interaction between various processes creates grooves which eventually obliterate between weeks 7 and 20.15 Failed fusion between the maxillary process and the undifferentiated facial prominence leads to various degrees of embryonic fissure defect, facial dysmorphogenesis, midfacial hypoplasia, orofacial clefts, intercanthal defect, sinuses hypoplasia and many more. The underdevelopment of the maxillary process also affects the medial migration of the eyes from 160° to a final position of 72° between the optic axes.14 The retarded maxillary growth produces some degree of hypertelorism.
Our finding of 73% prevalence of ocular abnormalities in PL is consistent with that reported by Khoo and Boo-Chai (70.5%).4 On the contrary, English17 noted a lower prevalence (44.0%) of ocular abnormalities.
Eyelid coloboma represents the most common ocular abnormality in this study. The present study showed higher involvement of the lower eyelid (67.7%). Our result is at odds with studies18 concluding more of upper eyelid involvement (93%) in congenital eyelid colobomas. These studies included both isolated colobomas and colobomas coexistent with other craniofacial anomalies. The latter has its origin earlier in the embryogenesis. Craniosynostosis syndrome and cleft disorders contributing to lower eyelid colobomas were under-represented. This introduces a probable source of discrepancy with the present results.
The incidence of ocular coloboma reported in ophthalmic literature is 36% for the anterior segment, 39% for the posterior segment and 24% for both the anterior and posterior segments.19 The frequency of iris coloboma (22.4%) and retinochoroidal coloboma (12.9%) in our study is much lower. Expertise bias while assessing for ocular anomalies at a younger age in the present cohort may explain the difference.
Hypertelorism documented in the current study is lower than that reported by Sakamoto et al20 (25.3% vs 54%). Illusory hypertelorism without radiographic or CT confirmation is difficult to rule out. Thus, hypertelorism adopted in present study was the one reported by respective authors of case reports or case series included in our study. We did not perform any extra assessment on the specialised image programming as done by Sakamoto et al.20 They devised a specialised image programming to exclusively study hypertelorism. This discripency in photographic adaptation of hypertelorism from literature has likely resulted in under-represention of a subset of hypertelorism in our case series. Hence direct comparison between both studies is inappropriate. Sakamoto et al20 reported cases of hypotelorism, of which nine had cyclopia. All were stillborn or died at an early age with severe holoprosencephaly. It is also worth mentioning the case of a neonate who survived with cyclopia with associated panophthalmitis.6
In our cohort, 35% (7 cases) of micro-ophthalmia/anophthalmia had bilateral involvement'. Ophthalmic abnormalities are not restricted to the same side of PL as the other side can also be affected. Biber21 in his review on PL quoted a case - featuring contralateral malformations. Guion-Almeida et al22 in a series of cerebro-ocular nares syndrome (CONS) defined a proboscis-like nare. Case number 9 in their series had ocular manifestations on another side of the proboscis-like nares. These observations highlight the possibility of contralateral involvement of ocular malformations as opposed to the popular belief of ipsilateral predilection in PL. The CONS series had higher frequency of brain abnormalities in cases with micro-ophthalmia/anophthalmia and hypertelorism. Including these cases in the present cohort may have influenced and skewed the association results.
In the present study, the associated anomalies in the brain (56.2%) and faces (54.7%) are higher compared with a study by English17 (19% and 38%, respectively). The Guion-Almeida et al study22 had documented serious brain abnormalities and profound facial oddity. These include a wide forehead, abnormal frontal hairline, high narrow palate and elongated philtrum.
Our study revealed a significant association between brain abnormalities or systemic abnormalities and hypertelorism and micro-ophthalmia/anophthalmia (p=0.000). To our interest, brain or systemic severity did not show an association with cumulative ocular abnormalities (p=0.249) or intraocular abnormalities (p=0.991). Hence, hypertelorism and micro-ophthalmia/anophthalmia reflect a diagnostic value. Their presence reinforces the need for neurological imaging and assessment. A positive association was noted between cumulative systemic abnormalities and cumulative ocular abnormalities (p=0.001). This suggests imploring a comprehensive ophthalmic evaluation in patients with systemic manifestations.
There are a few limitations to the present study. PL with other fatal malformations was excluded from this study. Such exclusion may have drawn a cohort of less affected subjects. The main potential for bias comes from the normal inference of unspecified ocular features. This may produce an understated prevalence of anomalies.
