Midbrain-Hindbrain Involvement in Septo-Optic Dysplasia

Discussion

The wide spectrum of imaging findings in SOD includes variable combinations of abnormalities of midline brain structures, the pituitary gland, optic nerves and eyes, olfactory bulbs, and other brain structures.¹⁰ Midline brain defects classically consist of complete or partial absence of the septum pellucidum with fused midline fornices (60% of cases) and/or corpus callosum abnormalities, such as agenesis, dysplasia, or hypoplasia.^1,10,11 Pituitary gland malformations include anterior pituitary hypoplasia, ectopic posterior lobe, and/or thin or interrupted pituitary stalk.³ Optic nerve hypoplasia is frequently associated with ocular anomalies such as coloboma, anophthalmia, and microphthalmia.¹² The olfactory bulbs may be absent or hypoplastic.¹³ Other common associations include schizencephaly (so-called SOD-plus), gray matter heterotopia, polymicrogyria, and hippocampal malformations.^14⇓–16

MH abnormalities have not been described in patients with SOD to the best of our knowledge. Qualitative assessment of MH structures in the present study revealed abnormalities in 55% of patients, especially in the corpus callosum agenesis subgroup and in patients with pituitary gland abnormalities. Careful measurement and comparison of the height and AP diameter of midbrain, pons, medulla, and vermian height in patients with SOD versus healthy controls confirmed the visual analysis. Hypoplasia of the pons was the major finding, leading to a significantly higher midbrain to pons ratio compared with controls. Moreover, hypoplasia of the vermis and medulla was also associated, resulting in a globally small hindbrain. The term “hypoplasia” refers to a condition of incomplete or arrested development in which an organ or part of it remains below the normal size. Generalized or segmental brain stem hypoplasia may be an isolated malformative feature or part of a more complex MH malformation, such as pontocerebellar hypoplasia,¹⁷ horizontal gaze palsy with progressive scoliosis,¹⁸ pontine tegmental cap dysplasia,¹⁹ and anteroposterior or dorsoventral MH patterning defects.^20,21 More frequently, brain stem hypoplasia is identified in patients with cerebral malformations such as congenital muscular dystrophies,²² lissencephalies,²³ or cerebral commissural anomalies.²⁰ As previously described in other MH malformations,²⁴ we found that cognitive impairment or developmental delay was more frequent in patients with SOD with small hindbrain, worsening the prognosis and impairing rehabilitative strategies.

Recently, mutations in OTX2 and FGF8 genes have been described in patients with SOD.^2⇓–4 Interestingly, OTX2 and FGF8 play an important role both in the development of the anterior forebrain²⁵ and in the differentiation along the anteroposterior axis of the neural tube, with formation of the primary and secondary brain vesicles.²⁶ The latter process determines the correct regionalization of the forebrain (which rapidly divides into telencephalon and diencephalon), mesencephalon (midbrain), and hindbrain (which further divides into the rostral metencephalon, ie, pons and cerebellum, and caudal myelencephalon, ie, medulla oblongata). This delicate embryologic process requires the orderly expression and interaction of several signaling molecules and the formation of patterning centers such as the isthmus organizer at the MH junction.²⁷ In particular, Otx2 is expressed in the midbrain both in mice²⁸ and humans,²⁹ whereas Gbx2 is expressed in the anterior hindbrain, with a shared border at the level of IsO.³⁰ In rodent fetuses, the formation and normal location of IsO depends on a delicate interplay between the expression of Otx2, Gbx2,^6,7 and Fgf8.³⁰ Animal models have shown that repression of Otx2 expression induces Gbx2 formation to establish the location of the MH junction rostrally, resulting in a short midbrain and long pons. On the other hand, overexpression of Otx2 shifts the MH junction caudally, resulting in an elongated midbrain with a small pons and vermis.²⁷ Similarly, alterations of Pax6 or En1/Pax2 will change the location of the diencephalic-mesencephalic junction.²⁷

Remarkably, 6 patients with SOD spectrum and hypoplasia of hindbrain structures also showed hypertrophy of the mesencephalic tectum with consequent aqueductal stenosis and triventricular hydrocephalus. Broccoli et al⁶ assessed the effect of ectopic expression of Otx2 on MH development in mutant mice, and noticed that the superior and inferior colliculi appeared enlarged and were shifted posteriorly in all analyzed mutants. Furthermore, 3 patients also showed evidence of agenesis of the epithalamus (ie, stria medullaris, habenular trigone, pineal gland, and posterior commissure). Larsen et al²⁹ recently demonstrated that Otx2 is expressed in the pineal gland at later stages in human fetuses. Gene ablation experiments in mice revealed that Otx2 is a key regulatory gene for the development of the pineal gland.³¹ Furthermore, agenesis of the pineal gland has been described in patients with mutations of PAX6 gene and congenital aniridia.^32,33 Intriguingly, PAX6 is another important gene involved in the AP patterning of the brain. In particular, in murine and chick models, the correct formation of the diencephalic-mesencephalic junction depends on the interaction of Pax6 from the diencephalon and En1/Pax2 from the rostral mesencephalon, with the contributing role of FGf8 that induces forebrain cells to secrete Pax6.²⁷ Webb et al³⁴ recently studied the 24-hour melatonin profiles in 6 patients with SOD and sleep disorders. Interestingly, 2 children appeared to produce virtually no melatonin throughout the 24-hour period of measurement. These findings raise the suspicion of a possible correlation between pineal gland agenesis and abnormally reduced melanin production in patients with SOD, which awaits confirmation in prospective studies.

Finally, 1 patient in this study harboring a de novo deletion at 14q22.1–23.1 presented with a short, small midbrain with elongated pons and enlarged superior cerebellar vermis, suggesting an abnormality of MH anteroposterior patterning due to rostral misplacement of the IsO.^20–21 This patient also had right anophthalmia and left colobomatous microphthalmia, small corpus callosum, bilateral hippocampal malformation, and hypoplasia of the anterior pituitary lobe with an ectopic posterior lobe. Interestingly, the 14q22.1–23.1 deletion includes the Otx2 gene, supporting the hypothesis that loss of Otx2 expression may determine rostral misplacement of the IsO also in humans. OTX2 heterozygous mutations or deletions in humans have been linked to severe ocular malformations associated with forebrain abnormalities such as hippocampal and callosal malformations, and combined or multiple pituitary hormone deficiencies.¹² However, no careful description of MH structures has been provided so far in these patients. We reviewed the available brain MR midline sagittal images including the posterior cranial fossa of previously reported patients with Otx2 mutations^{35⇓⇓–38} or chromosome 14 deletions including Otx2,^{39⇓⇓⇓–43} and we recognized a similar midbrain hypoplasia with a long pons and large superior vermis in 5 patients.^{35,36,40,41,43} We therefore suggest that MH abnormalities may have been underestimated in patients with Otx2 mutations or deletion; further studies on larger series are awaited to address this hypothesis.

This study has several limitations, mainly including its retrospective design, the relatively small sample size, and the incomplete genetic assessment. Furthermore, the functional role and clinical implications of MH abnormalities in patients with SOD remain uncertain, and require further prospective studies.