Marie-France Bonnetain

Christelle Rougeot-Jung

Catherine Sarret

Laurence Lion-François

Olivier Revol

Emeline Peyric

Juan Velazquez-Dominguez

Anne Miret

Massimiliano Rossi

Mona Massoud

Laurence Lion- François

Hélène Laurichesse -Delmas

Laurent Guibaud

Vincent Des Portes

C Rouget-Jung

Normal intellectual skills in patients with Rhombencephalosynapsis

Keywords: rhombencephalosynapsis, cognitive outcome, intellectual abilities, attention deficit hyperactivity disorder, prenatal counselling, vermis, magnetic resonance imaging

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Introduction

Rhombencephalosynapsis (RES) is a rare cerebellar malformation defined by partial or complete agenesis of the vermis and fusion of the cerebellar hemispheres and dentate nuclei [START_REF] Garel | The fetal cerebellum: development and common malformations[END_REF][START_REF] Ishak | Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity[END_REF][START_REF] Poretti | Fetal Diagnosis of Rhombencephalosynapsis[END_REF][START_REF] Guibaud | Fetal ventriculomegaly: diagnostic, ethical and semantic considerations[END_REF][START_REF] Aldinger | Rhombencephalosynapsis: Fused cerebellum, confused geneticists[END_REF].

RES is frequently associated with other abnormalities (aqueductal stenosis, mesencephalosynapsis, holoprosencephaly, corpus callosum dysgenesis, microlissencephaly, pontocerebellar hypoplasia, extra-cerebral malformations, and chromosomal anomalies) [START_REF] Sener | Unusual MRI findings in rhombencephalosynapsis[END_REF][START_REF] Pavone | A complex brain malformation syndrome with rhombencephalosynapsis, preaxial hexadactyly plus facial and skull anomalies[END_REF][START_REF] Pasquier | Rhombencephalosynapsis and related anomalies: a neuropathological study of 40 fetal cases[END_REF][START_REF] Mak | MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis[END_REF][START_REF] Saugier-Veber | Pontocerebellar hypoplasia with rhombencephalosynapsis and microlissencephaly expands the spectrum of PCH type 1B[END_REF] or occurs as a syndromic form, such as VACTERL syndrome [START_REF] Pasquier | Rhombencephalosynapsis and related anomalies: a neuropathological study of 40 fetal cases[END_REF], or the recently described MN1 or gene-related syndromic RES [START_REF] Mak | MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis[END_REF]. The most common syndrome related to RES is Gomez-Lopez-Hernandez syndrome (GLHS) or cerebello-trigeminal-dermal dysplasia, comprising scalp alopecia, inconsistent trigeminal anaesthesia and craniofacial features, short stature and kidney malformation [START_REF] Poretti | Gomez-Lopez-Hernandez syndrome: an easily missed diagnosis[END_REF][START_REF] Sukhudyan | Gómez-López-Hernández syndrome: reappraisal of the diagnostic criteria[END_REF][START_REF] Rush | Four new patients with Gomez-Lopez-Hernandez syndrome and proposed diagnostic criteria[END_REF].

Apart from the very rare syndromal genetic constellation (e.g associated with mutations in MN1) patients with RES and GLH are sporadic observations and the recurrence risk for a couple is extremely low [START_REF] Aldinger | Rhombencephalosynapsis: Fused cerebellum, confused geneticists[END_REF].

Classically, patients with RES present with motor developmental delay, ataxia, and the characteristic "figure-of-eight" head shaking [START_REF] Tully | Persistent figureeight and side-to-side head shaking is a marker for rhombencephalosynapsis[END_REF][START_REF] Accogli | Teaching Video NeuroImages: Figure 8 head-shaking stereotypy in rhombencephalosynapsis[END_REF]. The range of cognitive outcome is very large, from profound intellectual disability to normal IQ. Syndromic forms of RES, such as VACTERL, are associated with severe cognitive prognosis [START_REF] Ishak | Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity[END_REF], but patients with GLHS may have a good cognitive prognosis if no additional brain malformation exists [START_REF] Ishak | Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity[END_REF][START_REF] Sukhudyan | Gómez-López-Hernández syndrome: reappraisal of the diagnostic criteria[END_REF].

If such condition can be diagnosed postnatally, advances in prenatal imaging have resulted in an increasing number of prenatal diagnoses of abnormalities of the posterior fossa, including RES [START_REF] Massoud | Prenatal imaging of posterior fossa disorders. A review[END_REF]. In foetal medicine practice, RES is diagnosed in two very different settings. Indeed, RES can be diagnosed when facing severe ventriculomegaly in the early second trimester when RES is associated with other cerebral malformation, involving especially the mesencephalon and diencephalon, as we have previously described [START_REF] Cagneaux | Severe second-trimester obstructive ventriculomegaly related to disorders of diencephalic, mesencephalic and rhombencephalic differentiation[END_REF]. In such setting, most cases lead to termination of pregnancy due to severe obstructive ventriculomegaly of poor postnatal outcome. On the other hand, RES can be prenatally diagnosed on the basis of an isolated reduced transverse cerebellar diameter (TCD), detected in the second or last trimester, without severe ventriculomegaly or associated malformation, leading to the diagnosis of apparently isolated RES. In such setting the diagnosis can be easily overlooked.

When apparently isolated RES is detected, prenatal counselling remains challenging due to confusing/poor literature regarding the post-natal outcome: short follow-up and lack of cognitive assessments with psychometric batteries, which have been reported for only nine published cases [START_REF] Verri | Oral self-mutilation in a patient with rhombencephalosynapsys[END_REF][START_REF] Montull | Neuroradiological and clinical findings in rhombencephalosynapsis[END_REF][START_REF] Bell | Normal IQ in a 55-year-old with newly diagnosed rhombencephalosynapsis[END_REF][START_REF] Prakash | Psychiatric comorbidities in Dandy-Walker variant disorder[END_REF][START_REF] Michael | Reactivity to visual signals and the cerebellar vermis: Evidence from a rare case with rhombencephalosynapsis[END_REF]. In attempt to overcome this issue, we report the radiological, developmental and cognitive features of six individuals with apparently isolated RES at the time of diagnosis, including three detected in prenatal settings. Ataxia, dysmetria and fine motor skills were scored using a five-grade scale, according to the degree of disturbance of activities of daily living, adapted from Poretti et al. [START_REF] Poretti | Cognitive outcome in children with rhombencephalosynapsis[END_REF]: [START_REF] Garel | The fetal cerebellum: development and common malformations[END_REF] severe: unable to walk unassisted; (2) moderate: wide-based gait, frequent falls, and overt dysmetria; (3) mild: infrequent falls, gross motor problems, and fine motor difficulties in drawing or writing; (4) minimal: very mild gait ataxia or dysmetria on neurological examination without consequences on daily-life activities; and (5) no complaint and normal neurological examination.

Materials and methods

A

Intelligence Quotient (IQ) was established according to Weschler Intelligence Scales: the Wechsler Pre-school and Primary Scale of Intelligence 3 rd edition (WPPPSI-3) [START_REF] Wechsler | WPPSI III Echelle d'intelligence de WECHSLER pour la période préscolaire et primaire -3 rd edition[END_REF], the Wechsler Intelligence Scale for Children 4 th edition (WISC-4) [START_REF] Wechsler | Echelle d'intelligence de WECHSLER pour enfants et adolescents -4 th edition[END_REF] and the Wechsler Intelligence Scale for Adults 4 th edition (WAIS-4) [START_REF] Wechsler | Echelle d'intelligence de WECHSLER pour adultes -4 th edition[END_REF]. Attention deficit hyperactivity disorder (ADHD) was diagnosed according to the DSM-IV criteria and KiTAP computerized battery [START_REF] Zimmermann | Testbatterie zur Aufmerksamkeitsprufung für Kinder (KITAP)[END_REF]). For Patient 5, the Psychomotor Development Index was obtained alongside the French Brunet Lézine Development Scale [START_REF] Josse | Echelle de développement psychomoteur de la première enfance. EAP (Editions et Applications psychologiques[END_REF].

Ethical issues. The clinical follow-up was performed within the frame of routine clinical visits and no further written consent was required from parents. Neither photographs nor blood samples were specifically required for the study.

Results

Twenty-three cases of RES were diagnosed during the inclusion period (figure 2, see also Table 5 suppl. data). Among the 12 pregnancies, 8 had obstructive VM. Only 4 fetuses had an apparently isolated RES, leading to one termination of pregnancy and three births. Among the 11 children diagnosed with RES after birth, 7 had a syndromic RES with other malformation and/or chromosomal anomaly. Only 4 had isolated RES. One case has already been published [START_REF] Michael | Reactivity to visual signals and the cerebellar vermis: Evidence from a rare case with rhombencephalosynapsis[END_REF] and this patient was therefore excluded from the series.

Finally, this series included six patients with apparently isolated RES at the time of diagnosis. Three were diagnosed in prenatal settings driven by a small Transverse Cerebellar Diameter (TCD) on foetal ultrasound without obstructive ventriculomegaly or obvious associated malformation. Three were referred postnatally based on clinical signs. Detailed clinical histories of the six cases are provided as supplementary material (see online supplementary data). Relevant clinical, cognitive and MRI findings are summarized in Tables 1-3 and Fig. 1,2.

Clinical features (Table 1). Among the three cases diagnosed postnatally, brain MRI was requested due to a delay in walking (Patient 2) and mild ataxia (Patients 3 and 6). The onset age for walking (from 17 to 36 months) was delayed in four patients. According to the ataxia/fine motor skills scale, Patient 1 had a mild disability due to motor and visuospatial dyspraxia with impaired writing (Table 2 and supplementary data); Patient 4 had minimal impairment with a transient delay in fine motor and graphic skills and subtle ataxia that did not impair walking in daily life; and Patients 2, 3, 5 and 6 had slightly delayed walking or transient ataxia that improved, with a normal neurological examination at the last visit. Three patients had stereotyped side-to-side head shaking and three had a strabismus. Two patients had growth hormone (GH) deficiency, including Patient 1 who fulfilled Gomez-Lopez-Hernandez (GLH) syndrome criteria.

Imaging data. All patients had postnatal brain MRI (Fig. 1). In all cases, the hemispheres were fused on the midline on coronal images, tangential to the most posterior part of the cerebellum (Fig. 1; C1-C6). On mid-sagittal images, neither the primary fissure nor the pre-pyramidal fissure was identified on the cerebellum (Fig. 1; A1-A6). One should note that although fusion of the two dentate nuclei is a cardinal feature of RES based on pathological specimens, this feature can only be clearly identified on MRI in neonates because of the hyperintensity of these two nuclei on T2weighted imaging (Fig. 1; B3, B5 [small arrows]) which disappears later in life.

We considered RES as complete (Patient 1, 4, and 6) if the inferior borders of the cerebellar hemisphere at the level of cerebellar tonsils were fused on the midline (Fig. 1; D1, D4, D6

[asterisk]) without identification of any incisure between the two cerebellar tonsils (Fig. 1 2 and Fig. 3, were quite homogeneous. IQ score was normal for four patients and high for one patient. The Working Memory and Processing Speed were weaker in patient 1 who had dyspraxia and ADHD. Other patients who had a deficit in fine motor skills improved with age. Interestingly, for Patient 5 who had a delay in walking, the developmental index improved from 12 to 24 months old with normal developmental skills in all domains and very good language abilities (Table 3). Three of five patients had ADHD based on DSM IV criteria. For two of them, the KiTAP computerized battery, performed at the age of five years and 11 years, respectively, showed sustained attention deficit, sensitivity to a distractor, mental flexibility deficit, motor inhibition deficit and impulsiveness.

Divided attention appeared to be spared (Table 2). Attention deficit was significantly improved on methylphenidate in both treated patients.

Discussion

In this study, we considered "apparently isolated RES" as RES without additional brain malformation, severe ventriculomegaly or chromosomal anomalies at diagnosis, especially when detected in prenatal settings. However, it has been reported that such a continuous series of associated congenital anomalies precludes RES from being clearly separated into distinct "syndromic" and "isolated" entities [START_REF] Aldinger | Rhombencephalosynapsis: Fused cerebellum, confused geneticists[END_REF]. Indeed, for Patient 1 of this series who was considered to have "apparently isolated RES" in prenatal settings, other malformations (heart, kidney, spina lipome, craniofacial dysmorphy) leading to GLHS were revealed only after birth. This pitfall of GLHS diagnosis in prenatal settings has been previously mentioned, since neuroimaging does not allow to distinguish between isolated RES and GLHS [START_REF] Poretti | Gomez-Lopez-Hernandez syndrome: an easily missed diagnosis[END_REF]. In previous series of patients with GLH, developmental outcome was variable, from severe cognitive disability to normal cognitive skills [START_REF] Ishak | Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity[END_REF][START_REF] Poretti | Gomez-Lopez-Hernandez syndrome: an easily missed diagnosis[END_REF]. Despite good intellectual abilities, additional motor and/or genital, urinary, and bowel dysfunction, which may occur in GLHS, should lead to careful investigation of extracerebral malformations, including spinal cord defect, on prenatal ultrasound. As far as we know, spinal cord defect has not been previously described in GLHS. Nevertheless, bladder dysfunction was reported in one patient [START_REF] Poretti | Gomez-Lopez-Hernandez syndrome: an easily missed diagnosis[END_REF] and tethered cord or lumbosacral myelomeningocele has been previously described with RES [START_REF] Aldinger | Rhombencephalosynapsis: Fused cerebellum, confused geneticists[END_REF][START_REF] Toelle | Rhombencephalosynapsis: clinical findings and neuroimaging in 9 children[END_REF][START_REF] Sener | Rhombencephalosynapsis and a Chiari II malformation[END_REF][START_REF] Weaver | Rhombencephalosynapsis: embryopathology and management strategies of associated neurosurgical conditions with a review of the literature[END_REF].

In search of prognostic factors, which should be useful in prenatal settings for couples facing an apparently isolated RES, we carefully analysed published case reports with reliable data on cognitive and motor outcome (Table 4). We excluded from this review published cases of RES associated with obvious major malformations contributing to a severe condition (holoprosencephaly, diffuse pachygyria, obstructive hydrocephaly due to pathologies of differentiation of the diencephalon or mesencephalon, multiple congenital anomalies, syndromic RES such as VACTERL, chromosomal defects, etc.). We did not include data from the largest series of 42 RES cases by Ishak et al. [START_REF] Ishak | Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity[END_REF], despite the fact that this was overall very informative, for three reasons: (1) detailed developmental and neurological data on individual cases were not available;

(2) outcome categories did not separate cognitive and motor skills; and (3) according to the authors, the cohort was likely skewed towards more severely affected subjects with associated abnormalities due to recruitment bias. Also, we did not include GLHS patients since a comprehensive review has already been published [START_REF] Poretti | Gomez-Lopez-Hernandez syndrome: an easily missed diagnosis[END_REF]. Finally, in addition to the six cases of this series, we reviewed 22 previously reported cases from 12 different publications, and classified the 28 patients into three groups (Table 4): (1) associated RES with subtle brain anomalies (such as a thin corpus callosum, fused fornices, heterotopia or focal cortical dysplasia, hippocampal dysplasia) (including our Patient 5); (2) RES with foetal/congenital hydrocephalus, that required a shunt (including our Patient 4); and (3) apparently isolated RES without associated brain anomalies, extracerebral malformations at diagnosis and/or shunted hydrocephalus after birth (including our Patients 1, 2, 3 and 6).

Concerning cognitive outcome, psychometric data were available in 15 patients [15-17, 19, 20] including the six patients of the present series. For the 13 other patients, cognitive outcome was classified according to three grades; "normal", "mild" and "severe" disability, based on available clinical data. Nineteen individuals (68%) had normal IQ or cognitive outcome, five (18%) had borderline functioning or mild intellectual disability and four (14%) had moderate to profound disability. Among the nine cases with apparently isolated RES, seven had normal cognitive skills and one had borderline IQ. The other patient described with a severe outcome was young (18 months) and no clinical or imaging data was available. Among the 13 cases with subtle brain anomalies, nine had normal cognitive skills, three had borderline functioning or mild intellectual disability and one had moderate disability. In the third group including six patients with shunted hydrocephalus, three had normal cognitive outcome and three had mild to profound intellectual disability.

Concerning motor outcome, we scored the 28 cases using a five-grade scale adapted from Poretti et al. [START_REF] Poretti | Cognitive outcome in children with rhombencephalosynapsis[END_REF], focusing on the degree of disturbance in daily life (Table 4). Among the 28 patients, functional data were not available for three patients with abnormal movements (tics), spastic paraplegia and seizures. Among the 25 other cases, eight (32%) had minimal impairment (very mild gait ataxia or dysmetria without consequences on daily-life activities) or no complaint at all, of whom four were classified as isolated RES; 10 (40%) had mild impairment (infrequent falls, gross motor problems, and fine motor difficulties in drawing or writing), who were equally divided between isolated RES and those with subtle brain anomalies; and four (16%) had moderate (widebased gait, frequent falls) and three (12%) severe (unable to walk unassisted) motor impairment, two of whom had shunted hydrocephalus. These data should, however, be considered with care, as the developmental trajectory of patients was not specified in most reported cases. Knowing that, in our series, four children who had delayed walking and ataxia improved with age, the motor impact of RES might be overestimated, especially for young children. These data highlight important questions addressing the crucial issue of prognostic factors associated with RES: for example, to what extent might subtle associated brain anomalies and shunted hydrocephalus influence the cognitive outcome of patients with RES? Regarding associated brain anomalies, the association between RES and aqueductal stenosis has already been underlined [START_REF] Barkovich | Rhombencephalosynapsis[END_REF], and a close examination of the third ventricle, thalami, aqueduct of Sylvius and cerebellum is required in order to identify underlying pathologies of differentiation of the diencephalon, mesencephalon, and sometimes telencephalon, leading to severe outcome [START_REF] Ishak | Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity[END_REF][START_REF] Poretti | Cognitive outcome in children with rhombencephalosynapsis[END_REF][START_REF] Cagneaux | Severe second-trimester obstructive ventriculomegaly related to disorders of diencephalic, mesencephalic and rhombencephalic differentiation[END_REF]. Indeed, in the large series of 42 patients [START_REF] Ishak | Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity[END_REF], a variable degree of mesencephalosynapsis was reported in 52% of subjects, that ranged from isolated fusion of inferior or superior colliculi, to a mass-like fusion of the entire mesencephalon, extending from the superior cerebellar peduncles up to the level of the posterior commissure. Thirty percent of their subjects also had a lack of olfactory bulbs, suggesting associated forebrain defects.

One of the most frequent associated malformations is corpus callosum dysgenesis, found in more than a third of non-isolated RES [START_REF] Pasquier | Rhombencephalosynapsis and related anomalies: a neuropathological study of 40 fetal cases[END_REF]. Among the cases gathered in Table 4, it is difficult to determine the mechanism that might be responsible for a "thin corpus callosum", which may be due to being stretched by an enlarged third ventricle [START_REF] Cagneaux | Severe second-trimester obstructive ventriculomegaly related to disorders of diencephalic, mesencephalic and rhombencephalic differentiation[END_REF] or due to primitive corpus callosum dysgenesis or an insult. Associated thin white matter [START_REF] Danon | Rhombencephalosynapsis diagnosed in childhood: clinical and MRI findings[END_REF] might be a better clue for a reduced and pathological axonal network. A large majority (eight out of nine) of cases described with a thin or hypoplastic corpus callosum were associated with enlarged ventricles or hydrocephalus (Table 4). Our Patient 5, with a short rostrum and splenium of corpus callosum and normal ventricles, is an exception.

Accordingly, in the large series of 42 patients with RES [START_REF] Ishak | Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity[END_REF], most anterior commissure abnormalities (14/16) were secondary to obstructive hydrocephalus, rather than due to abnormal brain development. Nevertheless, regardless of the mechanism responsible for thin corpus callosum associated with RES, only five of nine patients had good cognitive outcome compared to eight of nine patients with normal ventricle size and corpus callosum (Table 4). The cognitive impact of fused quadrigeminal plates [START_REF] Demaerel | Uncommon posterior cranial fossa anomalies: MRI with clinical correlation[END_REF] or fused fornices [START_REF] Montull | Neuroradiological and clinical findings in rhombencephalosynapsis[END_REF][START_REF] Poretti | Cognitive outcome in children with rhombencephalosynapsis[END_REF] is still questionable, since cognitive outcome of the three published cases varied from mild intellectual disability to normal IQ. In the series of Ishak et al. [START_REF] Ishak | Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity[END_REF], 8/13 patients with fused fornices (62%) had "mild disability" vs 12/14 patients (86%) with normal fornices.

Ishak et al.

(2) proposed an anatomical classification, dividing RES into four types according to both the presence of nodulus and partial presence of anterior/posterior vermis, and suggested that the degree of clinical severity might be correlated with the degree of cerebellar fusion. However, associated forebrain (16/42) or midbrain malformations or aqueductal stenosis (22/42) with major hydrocephalus were also described in most patients of this series, which might have influenced the outcome. Moreover, in prenatal settings, the visualization of the precise degree of agenesis of the vermis on foetal MRI might be challenging for radiologists, in particular, to identify the vermian fissure and lobulation [START_REF] Guibaud | Prenatal diagnosis of « isolated » Dandy-Walker malformation: imaging findings and prenatal counselling[END_REF]. Thus, in our study, we classified patients into only two subtypes: complete RES (Patient 1, 4, 6) (Fig. 1; D1, D4, D6), and partial RES (Patient 2, 3, 5) based on the presence of an incisure between two cerebellar tonsils (Fig. 1; D2, D3, D5). Since all had good cognitive skills, we did not identify any difference in cognitive outcome related to the subtype of RES (partial or complete) in this small series.

In our series, four patients had strabismus and three had head nodding. In the series of Poretti et al. [START_REF] Poretti | Cognitive outcome in children with rhombencephalosynapsis[END_REF], one patient had horizontal nystagmus, one had convergent alternating strabismus and four out of five patients exhibited rhythmical, regular, intermittent head stereotypies corresponding to lateral head nodding. In all cases, these improved in frequency and intensity over the course of several years, but never disappeared. Strabismus and frequent head stereotypies may contribute to impaired social interaction with peers [START_REF] Poretti | Cognitive outcome in children with rhombencephalosynapsis[END_REF] and might require psychological support. Despite a normal IQ, three patients of our series presented with ADHD. Attention deficit and/or hyperactivity has previously been described in four out of five cases by Poretti et al. [START_REF] Poretti | Cognitive outcome in children with rhombencephalosynapsis[END_REF], and in cases with other cerebellar malformations [START_REF] Prakash | Psychiatric comorbidities in Dandy-Walker variant disorder[END_REF][START_REF] Torres-Mohedas | Joint presentation of facial hemangioma, posterior fossa malformation, and carotid-vertebral hypoplasia (Pascual-Castroviejo syndrome II): report of 2 new cases[END_REF][START_REF] Bhattacharya | A case of Dandy-Walker variant disorder associated with multiple neuropsychiatric comorbidities managed with behavioral therapy[END_REF]. Moreover, the volume of posterior and inferior vermis is smaller in patients with ADHD and correlates with the intensity of the disorder [START_REF] Berquin | Cerebellum in attention-deficit hyperactivity disorder: a morphometric MRI study[END_REF][START_REF] Castellanos | Quantitative brain magnetic resonance imaging in girls with attention-deficit/hyperactivity disorder[END_REF].

Previous authors have hypothesized that the vermis could modulate attentional processes through the fronto-striato-cerebellar tract which connects the prefrontal cortex, the thalamic nuclei, the pons and the cerebellum [START_REF] Doyon | Distinct contribution of the cortico-striatal and corticocerebellar systems to motor skill learning[END_REF][START_REF] Stoodley | Functional topography of the cerebellum for motor and cognitive tasks: an fMRI study[END_REF][START_REF] Kelly | Toward systems neuroscience of ADHD: a meta-analysis of 55 fMRI studies[END_REF]. In a previous study, we described a particular attentional profile in a patient with isolated RES [START_REF] Michael | Reactivity to visual signals and the cerebellar vermis: Evidence from a rare case with rhombencephalosynapsis[END_REF]. Reactivity to a visual signal, which appeared at the same time as a distractor, was normal but the patient made more mistakes, possibly due to impulsive reactions and a deficit in motor inhibition. Distraction before the apparition of the target did not disturb the patient, however, the ability to detect the visual distractor, which appeared after the target, was reduced [START_REF] Michael | Reactivity to visual signals and the cerebellar vermis: Evidence from a rare case with rhombencephalosynapsis[END_REF]. These data are comparable to the attentional profile of three of our patients (Table 1). Attentional flexibility, motor inhibition and sustained attention were impaired and selective and divided attentions were preserved.

The vermis might participate in modulating the excitability of the cerebral area, which commands the preparation and control of motor response and attentional flexibility processes. In RES patients, the ability to recognize a pertinent target is preserved. These data tend to support the hypothesis that the vermis has an inhibitory function on cerebral motor areas. Our understanding of the processes involved in attention disorders may enable targeted and early cognitive rehabilitation of patients.

Conclusion

These six new cases of RES with good cognitive outcome reinforce the previously recognized observation that most RES patients without obvious associated malformation and/or obstructive hydrocephaly and/or chromosomal anomaly seem to have preserved intellectual abilities, which is a crucial point for couples' decision following prenatal diagnosis. Nevertheless, ADHD is observed in half of the cases. These data also highlight the involvement of the vermis in attentional processes.

Further follow-up of the rare patients born after a prenatal diagnosis of RES is mandatory, in order to more accurately evaluate the rate of preserved intellectual development and associated motor and attention deficit.

Legends of Tables and Figures

  retrospective study was conducted at the University Hospital of Lyon from 2003 to 2018, which aimed to provide a description of the cognitive outcome of all patients with apparently isolated RES. Children were included through two different settings, based on: (1) prenatal detection of a reduced TCD on foetal ultrasound leading to the diagnosis of "apparently isolated" RES on foetal MRI; or (2) postnatal diagnosis of isolated RES on brain MRI indicated for developmental delay or abnormal movement of the head. Inclusion criteria were an unequivocal diagnosis of RES on postnatal brain MRI, with fusion of the cerebellar hemispheres across the midline, as judged on axial plane, and transverse folial orientation on posterior coronal MRI sections (Fig. 1). Exclusion criteria were additional anomalies at diagnosis (cerebral or extra-cerebral malformation) and chromosomal anomalies. More specifically, fetuses with severe ventriculomegaly (15 mm or more) and/or aqueductal stenosis were excluded. Minor (10-11mm) or moderate (12-14 mm) foetal ventriculomegaly was not considered an exclusion criterion. Clinical data were collected from the clinical records: age at diagnosis, sex, ante-perinatal features, clinical signs at diagnosis, clinical examination, treatment, cognitive assessment, schooling and brain MRI.

  ; D1, D4, D6 [large arrow]), and RES as partial (Patient 2, 3, 5) when an incisure between two cerebellar tonsils was present (Fig. 1; D2, D3, D5), with identification of a small nodulus between them in some cases (Fig. 1; D2 [thin white arrow]). Other visible abnormalities were spinal cord lipoma (Patient 1; data not shown) and ventriculomegaly (patient 4 who required a ventriculoperitoneal shunt and patient 2 with mild VM). Despite a normal length of the corpus callosum (10e p), a short splenium and rostrum was noteworthy in Patient 5. No other associated brain malformation, such as thalami fusion or grey matter heterotopia, was revealed on postnatal MRI. Cognitive assessments: Five patients had an IQ assessment between 5 and 21 years old (WPPSI-III or WISC-IV or WAIS-IV). The cognitive profiles, detailed in Table

Fig. 1 .

 1 Fig. 1. MR images of Patient 1 to 6 performed at nine years, 19 months, 2.5 years, 15 days, seven days and four years, respectively. A1-A6: Mid-sagittal T1-(A1, A2, A6) or T2 -(A3, A4, A5) weighted MR images demonstrating, in all cases, an absence of both primary and pre-pyramidal fissures. Note the short splenium and rostrum of the corpus callosum in Patient 5 (A5). B1-B6: Axial T2-weighed (B1, B2, B6) or FLAIR (B3, B4, B5) MR images showing fusion of cerebellar hemispheres without identification of any vermian structure. Note that fusion of the two dentate nuclei is clearly identified only in Patient 4 and 5, due to the hyperintensity of the nuclei in

Fig. 2 .

 2 Fig. 2. Flow chart of patients with a diagnosis of RES during the inclusion period.

Fig. 3 .

 3 Fig. 3. Intellectual Quotient scores of Patients 1 to 4 and 6.

( 1 )Table 3 .

 13 VCI: Verbal Comprehension Index or Verbal Index (WPPSI-III); (2) PRI: Perceptual Reasoning Index or Performance Index (WPPSI-III); (3) WMI: Working Memory Index (4) PSI: Processing Speed Index or Processing Speed quotient (WPPSI-III), (5) special needs with teaching assistant. Developmental Index (Brunet-Lezine Scale) for Patient 5, at 12 and 24 months old.

  further cognitive assessment published by Poretti et al. (27); Patient 4, who had confounding factors (foetal valproate exposure and hypoxic ischemic encephalopathy); and Patient 5 who was lost to follow-up. ** Truwit et al. [41]: two patients were not included in this table; Patient 2, who had microcephaly and 2q deletion; and Patient 3 who had a fusion of the thalami (diencephalosynapsis). *** Hydrocephalus was considered when shunt surgery was required. Otherwise, ventriculomegaly was mentioned.

Table 1 .

 1 Clinical and radiological features of the six patients.

Table 2 .

 2 Cognitive features of the five older patients.

Table 4 .

 4 Published case reports with reliable data on cognitive and motor outcome.(n): degree of disturbance scale, adapted from Poretti et al.[START_REF] Sener | Rhombencephalosynapsis and a Chiari II malformation[END_REF]. Nyst: nystagmus; strab: strabismus. * Toelle et al.[START_REF] Toelle | Rhombencephalosynapsis: clinical findings and neuroimaging in 9 children[END_REF]: three patients of this series were not reported in this table; Patient 1, who had

Acknowledgments

The authors thank Oliver Gubbay for language editing. We would especially like to thank the patients and families for their involvement in the clinical follow-up.

Abbreviations

[vincent.desportes@chu-lyon.fr]; Phone: 33 [START_REF] Guibaud | Fetal ventriculomegaly: diagnostic, ethical and semantic considerations[END_REF]