MR Imaging Diagnosis of Diencephalic-Mesencephalic Junction Dysplasia in Fetuses with Developmental Ventriculomegaly

Discussion

We described a relatively large series of fetuses with second-trimester obstructive ventriculomegaly associated with clear features of DMJ dysplasia. Our cohort demonstrates that DMJ dysplasia could already be detected before gestational week 24 and that it has to be included among the causes of early developmental hydrocephalus. Fetal ventriculomegaly is a relatively common finding, occurring in approximately 1% of fetuses on sonography and in 1 of 1000 live born neonates.⁴ Conversely, DMJ dysplasia is probably rare, though it may be underestimated in cases without ventriculomegaly. The role of MR imaging in detecting brain anomalies in fetuses with ventriculomegaly is well established. Griffiths et al⁷ demonstrated a 17% risk of finding other brain abnormalities in fetuses with a confident sonography diagnosis of isolated ventriculomegaly. More recently, Barzilay et al⁸ showed that in fetuses with ventriculomegaly, the MR detection rate of minor and major brain findings increases with each millimeter increase in ventricle width. Various etiologies of fetal ventriculomegaly have been demonstrated, including acquired causes such as intraventricular hemorrhage, infection, or neoplasms.^4,5 When these have been excluded, radiologists must carefully assess MR images to identify additional brain abnormalities that may suggest a developmental/malformative cause of the hydrocephalus.⁹

DMJ dysplasia is a rare malformation first described in 6 children born from 3 consanguineous Egyptian families, with facial dysmorphisms, severe cognitive impairment, axial hypotonia, spastic quadriparesis, vasomotor instability, unexplained fever, and seizures.¹ So far, no causative genes have been linked to this condition. On imaging, DMJ dysplasia is characterized by a poorly defined junction between the diencephalon and the mesencephalon and by a ventral cleft contiguous with the third ventricle, producing a characteristic butterfly-shaped contour of the midbrain on axial images.^1⇓–3 Notably, MR imaging identified the butterfly sign and the abnormal relation between the midbrain and thalamic mass already at 20–21 gestational weeks in 6 fetuses of this series. Nonetheless, if not carefully sought, this finding may be overlooked, especially in the early gestational weeks. Therefore, to improve the detection rate of DMJ anomalies in earlier gestational stages, fetal MR imaging must be technically adequate, with perfectly oriented axial planes, and should not be hampered by fetal motion artifacts.

Developmental forms of hydrocephalus often have multiple points of obstruction.⁴ In the present series, cerebral aqueduct stenosis was confirmed in all cases with postnatal MR imaging or autopsy. Moreover, the cerebral aqueduct was scarcely visible in most fetuses of our series, suggesting that aqueductal stenosis could be the main cause of obstructive ventriculomegaly. Of note, the identification of the lumen of the cerebral aqueduct on MR imaging may not always be reliable in the early gestational weeks, often requiring follow-up studies for confirmation. Interestingly, in most of the present fetuses, the interthalamic adhesion was additionally enlarged and caudally displaced. The location of the interthalamic adhesion is highly variable in humans, but in most people, it lies at the center or in the anterior upper quadrant of the third ventricle, whereas it is located in the posterior inferior quadrant in fewer than 1% of cases.¹⁰ A recent computational study on CSF dynamics demonstrated that pressure in the third ventricle is higher when the interthalamic adhesion is located close to the cerebral aqueduct.¹¹ Partial or complete aqueductal stenosis associated with alterations of CSF flow dynamics within the third ventricle and abnormal WM development might thus explain the ventriculomegaly in these fetuses. In addition, the interthalamic adhesion hypertrophy is an important dysmorphic feature reported in several brain malformations, including Chiari II malformation, L1 syndrome with X-linked hydrocephalus,¹² and 6q terminal deletion syndrome.¹³ Notably, marked interthalamic adhesion hypertrophy may overlap with diencephalosynapsis, a rare malformation designating a complete or partial fusion of the thalami associated with secondary reduction of the lumen of the third ventricle,^14,15 and with rhombencephalosynapsis.⁶

Interestingly, all our presented fetuses were males, suggesting a possible X-linked inheritance pattern. Neuropathologic data from 138 fetuses and neonates genetically tested for X-linked hydrocephalus showed that 56 subjects (42%) harbored L1CAM gene mutations, and the remaining fetuses (58%) were classified into 4 distinct subgroups: 1) “L1-like” syndrome, including fetuses with no L1CAM mutations, but exhibiting characteristics of L1 syndrome (20%); 2) aqueductal atresia/forking spectrum, often associated with midbrain-hindbrain dorsoventral patterning defects (27%); 3) hydrocephalus associated with polymalformative syndromes, such as VACTERL-H (9%); and 4) hydrocephalus associated with isolated CNS malformations (44%).¹⁶ The L1CAM gene (Xq28) encodes a highly conserved type 1 transmembrane protein of the immunoglobulin superfamily that plays important roles in neuronal adhesion, neuronal migration, axonal growth, pathfinding, and fasciculation as well as in the development of the ventricular system and cerebellum. On imaging, L1 syndrome with X-linked hydrocephalus is usually characterized by bi- or triventricular dilation, aqueductal stenosis, enlarged quadrigeminal plate, interthalamic adhesion hypertrophy, and vermian hypoplasia.^12,17 Intriguingly, most of the fetuses in our series showed phenotypic and imaging characteristics similar to L1CAM-mutated fetuses. Moreover, postnatal MR imaging with DTI revealed corticospinal tract abnormalities in 2 cases, likely corresponding to the agenesis/fragmentation of the corticospinal tracts described in neuropathology cases of L1 and L1-like syndromes. Unfortunately, because of the lack of L1CAM genetic analysis in the present cases, we cannot establish whether DMJ dysplasia is caused by L1CAM mutations or if it belongs to the L1-like spectrum. Moreover, data on fetal MR features of L1 or L1-like syndrome are not available in the literature. DMJ features are likely to occur on a different genetic basis, and studies on genotype-phenotype correlation are definitively needed.

Finally, we observed pontine hypoplasia and small cerebellar vermis in most of the present fetuses, variably associated with moderate brain stem kinking. The differential diagnosis of prenatal ventriculomegaly and brain stem kinking has been recently widened to include several brain malformations, such as congenital muscular dystrophies, X-linked hydrocephalus caused by L1CAM mutations, microcephaly with lissencephaly and mid-hindbrain involvement, and tubulinopathies.^18,19 Taken together, these data indicate that a kinked brain stem is not a pathognomonic finding, but more likely an indicator of severe neurodysgenesis arising early in gestation and often associated with developmental hydrocephalus.¹⁸

The main limitation of our report is the lack of extensive genetic testing and histology investigation in all cases with pregnancy termination. Moreover, the possibility that fetal DMJ dysplasia cases without developmental obstructive ventriculomegaly may have been missed in our prenatal imaging search has to be taken into account.

In conclusion, a butterfly-shaped contour of the midbrain along with an abnormal spatial relation between the midbrain and thalamic mass may be detected on axial and sagittal sections, respectively, thus allowing an early prenatal diagnosis of DMJ dysplasia in fetuses with proximal obstructive ventriculomegaly. Among the rare causes of developmental hydrocephalus, DMJ dysplasia is likely to be an underestimated condition and seems to share several phenotypic features with the L1 and L1-like syndromes. Further studies on larger fetal populations with genotype-phenotype correlations are needed to clarify the causes, pathophysiology, and prevalence of DMJ dysplasia in the fetal population.