Characteristic MR Imaging Findings of the Neonatal Brain in RASopathies

Discussion

This is the first study that describes cranial MR imaging findings in neonates with a RASopathy. We have demonstrated that these neonates had characteristic acquired and structural abnormalities in the posterior fossa, including peripheral cerebellar hemorrhage, vermis hypoplasia, and a steep tentorial configuration compared with healthy controls. Moreover, these neonates also showed an increased incidence of cerebral white matter lesions, enlarged extracerebral spaces, simplification of the cortical folding, and structural corpus callosum abnormalities involving the splenium. Apart from anecdotal pediatric and adult case reports, data on global cerebral abnormalities in neonates with a RASopathy are rare in the literature. Brasil et al¹⁰ reported cerebral abnormalities, including isolated ventriculomegaly, posterior fossa anomalies, and cerebral atrophy in infants with NS. Few studies included cerebral MR imaging, and hypoplastic corpus callosum has only been described once in a patient with RASopathy with a mutation in the NF1 gene.¹¹ A vertical position of the splenium of the corpus callosum has also been reported in the literature.⁷ We have seen that the splenium of the corpus callosum showed a visually abnormal vertical configuration in 3 of our neonates and was underdeveloped in one. Furthermore, an enlarged extracerebral space, which was previously reported by Gripp et al⁷ in 1 patient, and delayed gyrification of the cerebral cortex were present in most of our patients. To the best of our knowledge, these are all novel contributions.

Total brain tissue grows linearly prenatally, and Hüppi et al¹² demonstrated an almost 3-fold increase in the global brain volume between 29 and 41 weeks postconception using volumetric MR imaging measures. The inclination of the fetal tentorium gradually increases during pregnancy, because the rate of the cerebellar growth exceeds the rate of the occipital cerebral growth.¹³ However, during postnatal development, the tentorium moves inferiorly while progressively decreasing the TA.¹⁴ We found that the TA of the neonates with a RASopathy was significantly higher than that of healthy controls at similar postmenstrual ages. An increased TA reflects the vertical configuration of the tentorium; however, because we have seen a negative correlation between vermis height and TA, an increased TA in these patients can be explained by the effect of a genetic disorder causing disruption of developmental processes, resulting in a permanent change in the morphology of the cranium with an effect on the growth of other structures, as defined previously.^9,15,16

Bony structures of the skull base also undergo changes, namely retroflexion of the basicranium in the intrauterine and flexion in the postnatal period. These changes are reflected by an increase in the cranial base angle during fetal development and a subsequent decrease in the postnatal period.^14,17 Any anomaly during the orderly posteroanterior ossification of the cranial structures can interfere with normal formation of the bones and soft tissues and may result in an abnormal configuration.^18,19 The RAS/mitogen-activated protein kinase pathway plays a vital role in regulating components that are critical to normal development, and it is not surprising that a dysregulation in this pathway has deleterious effects on both embryonic and later stages of development, with implications on bony structures and cerebral tissues.¹ It has been shown that patients with NS have various skull anomalies.^3,20 Addissie et al²¹ reported a 2-month-old female infant with NS who developed craniosynostosis, and Ueda et al⁹ reported a series of 9 infants with a RASopathy and craniosynostosis. It has also been shown that infants with Costello syndrome had bone abnormalities resulting in macrocrania.⁵ In the present study, we have demonstrated that the cranial base angles of the infants with RASopathy were markedly depressed, a finding that reflects the abnormal skeletal development of the basicranium. Furthermore, a significantly increased infratentorial angle also confirms the deviant cranial cavity floor extending posteriorly, as shown in our study. Although the detailed pathophysiologic mechanism remains unknown, we speculate that rather than acquired lesions such as hemorrhages, these bone abnormalities and consequently changed angulations may result in the anomalous formation of the posterior fossa, which, in turn, changes the tentorial configuration.

In recent decades, cumulative evidence has shown that cerebellar function extends beyond sensorimotor control to relate the cerebellum with higher order functions such as attention, language, executive function, and cognition.^22,23 Preterm neonates with cerebellar hemorrhage can develop cognitive impairment, and the vermis is considered especially important for cognitive outcome.²⁴ Consistent with the literature, we have seen that the cerebellar vermis had an increase in size, as reflected by the increased vermis height, with increasing gestational age. Most interesting, we have found that neonates with a RASopathy had a small vermis compared with controls. Although the cerebellum of the infants in our study showed a trend toward a decreased diameter on coronal and axial planes, this was not statistically significant compared with healthy controls. We might speculate that the disrupting effect of these genetic conditions was more prominent on the central part of the organ, which contains more neural networks than the peripheral parts. Hemorrhages were seen in the peripheral parts of the cerebellum. It is unlikely that these hemorrhages contributed to the hypoplasia of the vermis in these infants because the hemorrhages were of recent onset and the hypoplasia was already present at birth. Further investigation is needed to find whether the hemorrhagic cerebellar lesions and the small vermis, as seen in our patients, can be used in the future as an imaging finding to better predict outcome; however, we would recommend a brain MR imaging in a neonate with a suspected diagnosis of a RASopathy, particularly when the neonatal course is complicated.

The present study has several limitations. First, due to the retrospective design of the study it is difficult to make causal inferences. Second, owing to the rarity of the severe neonatal presentation that requires NICU admission, the number of patients included in the study was relatively small. Finally, because most patients were diagnosed with NS, these results might not be generalizable for all RASopathies; however, NS is the most common type of these closely related disorders in the literature, hence, it is expected to see the same distribution in our cohort. Moreover, we have observed the same characteristic findings, consistently, in every patient in our study regardless of their final genetic diagnosis.

It is of interest that despite a wide range of neurodevelopmental outcomes in children with a RASopathy, no brain MR imaging studies have been performed previously to explore whether these could be explained by differences in brain structure and development. Our data may suggest that early MR imaging could help to better prognosticate outcome. The neonates included in our study were at the severe end of the spectrum because they required admission to a NICU. Thus, further studies are needed on those with a less complicated neonatal course. During the neonatal period, RASopathies can be challenging to diagnose because characteristic morphologic findings may not be fully established and recognition of these neuroimaging findings should facilitate the diagnosis of these conditions.⁵ Our study provides novel neuroimaging information that could help neonatologists, neuroradiologists, and geneticists to suspect the diagnosis and be aware of the possible complications during their follow-up. Further studies are warranted to define the exact pattern of injury and malformation in these neonates and correlate their neuroimaging findings with their neurodevelopmental outcome.