Discussion

Patients with ONH/SOD make up one of the largest groups of patients with congenital visual impairment. The etiology of ONH/SOD remains unknown in most cases and appears to be multifactorial. ONH has been described in various syndromic, chromosomal, inherited, and de novo genetic disorders. Overall, genetic abnormalities account only for a very small fraction of cases (<1%) with ONH. ^{Reference Webb and Dattani2} Mutations in HESX, acting as a transcriptional repressor, was the first of a handful genes described as being causative of ONH/SOD in 1998. ^{Reference Dattani, Martinez-Barbera and Thomas6} Other genes include mutations in PAX6, SOX2, SOX3, and OTX2. ^{Reference Chen, Yin, Lewis and Schaaf38,Reference Ganau, Huet, Syrmos, Meloni and Jayamohan39}

Various neuroimaging abnormalities, and especially absent septum pellucidum and small pituitary gland size with or without hypopituitarism, have been described in patients with SOD. ^{Reference Riedl, Vosahlo and Battelino21,Reference Birkebaek, Patel and Wright23,Reference Severino, Allegri and Pistorio28,Reference Alt, Shevell, Poulin, Rosenblatt, Saint-Martin and Srour30,Reference Wadams, Gupta, Novotny and Tebben35,Reference Antonini, Grecco Filho, Elias, Moreira and Castro36} Table 2 summarizes some of the neuroimaging findings reported in 26 studies from 5 countries (Canada, USA, Europe, Japan, and Brazil) across four continents. ^{Reference Mohney, Young and Diehl9,Reference Atapattu, Ainsworth and Willshaw12–Reference Antonini, Grecco Filho, Elias, Moreira and Castro36} Most studies from the 1990s onward, when brain MRI resolution improved substantially, like our study confirmed the reduced sizes of the optic nerve(s) and optic chiasm on brain MRI in the majority of patients with ONH/SOD. ^{Reference Ward, Connolly and Griffiths20,Reference Cemeroglu, Coulas and Kleis29,Reference Alt, Shevell, Poulin, Rosenblatt, Saint-Martin and Srour30}

The clinical features of ONH/SOD are similar in both males and females. Therefore, we were not expecting to find an association between sex and any neuroimaging abnormality. The association of sex and laterality of the reduced optic nerves and chiasm sizes in our study is interesting but needs to be replicated before any conclusions can be drawn. Its significance is uncertain.

Our study, unlike most other studies, included details on the symmetry in addition to laterality of the reduced optic nerves and chiasm sizes on neuroimaging. The analysis revealed interesting associations among the abnormal neuroimaging features in patients with ONH/SOD (Table 3). As anticipated, both the symmetry and laterality of ONH and reduced chiasm size were concordant, as reported previously. ^{Reference Ward, Connolly and Griffiths20} Symmetric or asymmetric ONH (rather than unilateral ONH), and normal or symmetrically small optic chiasm (rather than asymmetric optic chiasm) were significantly more likely to be associated with other neuroimaging abnormalities. Other studies also reported that bilateral ONH was more likely than unilateral ONH to be associated with: more severe pituitary gland abnormalities and corpus callosum hypoplasia on MRI, ^{Reference Riedl, Vosahlo and Battelino21} and clinical or neuroimaging abnormalities. ^{Reference Mohney, Young and Diehl9,Reference Garcia-Filion, Almarzouki, Fink, Geffner, Nelson and Borchert17} However, some studies reported no association between ONH laterality and the presence of pituitary abnormalities, ^{Reference Qian, Fouzdar Jain, Morgan, Kruse, Cabrera and Suh19} or absent septum pellucidum, ^{Reference Garcia-Filion, Almarzouki, Fink, Geffner, Nelson and Borchert17} on MRI. In general, it appears that unilateral ONH, with or without an asymmetrically small optic chiasm, may potentially have a different etiology from bilateral ONH based on the associated neuroimaging features. This speculation deserves further study.

Absence of the septum pellucidum is associated with corpus callosum abnormalities but not pituitary gland malformation. ^{Reference Garcia-Filion, Almarzouki, Fink, Geffner, Nelson and Borchert17} Our study concurred with the latter finding only, since absent septum pellucidum was not associated with corpus callosum abnormalities among our patients.

NMD were significantly associated with all midline structural abnormalities reported in this study including symmetrically small optic chiasm size, but not ONH. Cortical malformations were also reported to occur more commonly in patients with midline abnormalities, ^{Reference Alt, Shevell, Poulin, Rosenblatt, Saint-Martin and Srour30} especially absent SP. ^{Reference Riedl, Vosahlo and Battelino21} These associations may be related to the etiology of SOD, for example, a hemorrhage occurring around 2–3 months postconception causing disruption of neuronal migration and at the same time interfering with the development of midline brain structures. ^{Reference Alt, Shevell, Poulin, Rosenblatt, Saint-Martin and Srour30}

The prevalence of the various other neuroimaging abnormalities reported in our study generally falls within the ranges described in other studies (Table 2). ^{Reference Mohney, Young and Diehl9,Reference Atapattu, Ainsworth and Willshaw12–Reference Antonini, Grecco Filho, Elias, Moreira and Castro36} In most studies, a small pituitary gland size was reported in less than 60% of patients and in many studies in about 30–55%, while ectopic posterior pituitary gland was described less frequently (<50%) and in many studies in 5–33% of patients. A wider range for the occurrence of absent septum pellucidum (17 and up to 100%) and a narrower prevalence range for abnormal corpus callosum (mostly 8–40%) have been reported across many studies. The wide ranges reported in Table 2 are likely due to the variable inclusion criteria among various study participants, source of the patients (i.e., general/specialized health care centers or clinics for example, neurology/endocrinology clinics), sample size, genetic/ethnic background of the patients, variable phenotype of SOD, selection bias of the study participants (those with more severe clinical or neuroimaging abnormalities are more likely to be included), the focus of the study (i.e., the neuroimaging abnormalities investigated), and type of study (i.e., clinical or radiological). ^{Reference Benson, Nascene, Truwit and McKinney13}

Several studies reported NMD in patients with ONH/SOD (typically <45% of the cases) and in many studies in about 1–20% of cases. Such patients have been described as having “SOD plus” by some authors. ^{Reference Alt, Shevell, Poulin, Rosenblatt, Saint-Martin and Srour30} NMD are not part of the inclusion criteria for the diagnosis of SOD. NMD were seen occasionally in our cohort (20%). In 13 of our 26 patients with NMD, both cerebral hemispheres were involved, which has been reported previously, ^{Reference Ward, Connolly and Griffiths20,Reference Alt, Shevell, Poulin, Rosenblatt, Saint-Martin and Srour30} suggesting a widespread abnormal process occurring during a critical period of cerebral hemispheres development. Such patients may have an acquired cause, at least in some cases, since some had more than one type of NMD. Indeed, two or more types of NMD have been reported in some patients with SOD including schizencephaly and polymicrogyria. ^{Reference Ward, Connolly and Griffiths20,Reference Alt, Shevell, Poulin, Rosenblatt, Saint-Martin and Srour30} The number of NMD types seen in some of our patients, varying between 1 and 3, and the laterality of NMD were not associated with the laterality of the small optic nerves or chiasm sizes on neuroimaging, suggesting that the two entities occur independently, that is, one abnormality does not seem to cause the other.

The significant associations between the absence of the olfactory bulbs-tracts/olfactory sulci and: corpus callosum abnormalities and the presence of heterotopia in intriguing and requires confirmation in future studies. Benson et al. reported that 42–44% of their 33 patients with SOD also had olfactory sulcus and/or olfactory bulbs-tracts hypoplasia, and that in some patients there was discordance between the two sides in the aforementioned abnormalities. ^{Reference Benson, Nascene, Truwit and McKinney13} In our study, a smaller percentage of our cases (8.6%) showed the absence of these structures and that there was full concordance between olfactory bulbs-tracts absence and olfactory sulci absence. In 18 of our cases, these structures could not be adequately assessed on neuroimaging. In addition, the study by Benson et al. noted that anterior falx dysplasia was present in 16 of their 33 cases with SOD. ^{Reference Benson, Nascene, Truwit and McKinney13} Several scans among our cases were not adequate in quality to assess for the presence and integrity of this structure.

Interestingly, all these abnormal inconstant midline features, together with absent septum pellucidum and corpus callosum or pituitary gland abnormalities, are shared with the various types of holoprosencephaly. However, failure of the prosencephalon to separate into two cerebral hemispheric to varying extents in holoprosencephaly is a distinct feature of this disorder. ^{Reference Fitz40}

ONH/SOD should be considered as a disease spectrum rather than discrete; albeit, somewhat related disease entities. The latter being: ONH with hypopituitarism, ONH with midline brain defects, or a triad of ONH, hypopituitarism, and midline brain defects, since variable clinical and neuroimaging features may or may not be associated with either unilateral or bilateral ONH. ONH should be considered the central feature of this disorder occurring with or without a variable spectrum of other neuroimaging features and/or hypopituitarism.

In addition to the importance of investigating the laterality of ONH, we have also shown that the symmetry of the reduced optic nerves and chiasm sizes should also be considered and evaluated in future studies. It remains to be proven whether the variable disease spectrum described is caused by different etiologies, for example, genetic or acquired disruption of brain development in utero occurring at different critical time periods, which ultimately determines the various phenotypes seen.