Rhombencephalosynapsis (ORPHA:59315)
A rare cerebellar malformation characterized by congenital complete or partial fusion of the cerebellar hemispheres, dentate nuclei, and middle cerebellar peduncles, and complete or partial absence of the vermis. It may occur as an isolated anomaly or with other malformations of the brain.
Epidemiology
More than 150 cases of rhombencephalosynapsis (RES) have been reported in the literature, 24% of which are reported as an isolated malformation. The prevalence remains unknown.
Clinical description
Onset is variable as rhombencephalosynapsis (RES) may be detected in the antenatal period or manifest later in childhood. Brain MRI typically reveals an underdeveloped or absent cerebellar vermis associated with a midline fusion of cerebellar hemispheres. Classically, patients with RES present with motor developmental delay, ataxia, and abnormal movements (e.g. diminished movement at birth, head rolling, oculomotor abnormalities, a characteristic ''figure-of-eight'' head shaking). The range of cognitive outcome is very large, from profound intellectual disability to normal IQ. Clinical presentation may vary from a mild phenotype of truncal ataxia with preserved cognition, to a severe form associating cerebral palsy, congenital hydrocephalus and intellectual impairment. Most RES patients without obvious associated malformation and/or obstructive hydrocephaly and/or chromosomal anomaly seem to have preserved intellectual abilities. Attention-deficit/hyperactivity disorder (ADHD) is frequently observed. Other associated brain malformations include aqueductal stenosis, mesencephalosynapsis, holoprosencephaly, corpus callosum dysgenesis, microlissencephaly, pontocerebellar hypoplasia.
Etiology
The genetic etiology of RES remains unknown and no teratogenic effect has been confirmed. Most cases are sporadic, with no chromosomal anomaly. The recurrence risk for a couple is extremely low. Syndromal genetic associations like de novo mutations in MN1 (MN1 C-terminal truncation syndrome; MCTT) or pontocerebellar hypoplasia with RES and microlissencephaly (homozygous variant in EXOSC3) are very rare.
Diagnostic methods
Diagnosis is confirmed by brain MRI which shows characteristic dysgenesis or agenesis of the cerebellar vermis, a midline fusion of the cerebellar hemispheres, dentate nuclei and in some cases the superior cerebellar peduncles, as well as variable supratentorial anomalies including absent septum pellicidum, dysplastic corpus callosum, aqueductal stenosis associated with hydrocephalus, dilated third and lateral ventricles, and a keyhole-shaped fourth ventricle. Malformation severity ranges from partial to complete rhombencephalosynapsis and includes an atypical form characterized by absent posterior vermis and residual anterior vermis.
Differential diagnosis
RES sometimes occurs as part of a syndrome such as VACTERL association or the recently described MCTT syndrome. The most common syndrome related to RES is Gomez-Lopez-Hernandez syndrome (GLHS). Differential diagnosis includes other disorders with brain/cerebellar malformations such as holoprosencephaly, Dandy-Walker syndrome and Joubert syndrome.
Antenatal diagnosis
Antenatal diagnosis is possible after 21 weeks of gestation, when cerebellar structures are well defined. Ultrasound may reveal enlarged cerebral ventricles, a common indication for fetal MRI which may in turn show typical findings of RES. Follow-up fetal MRI should be considered in uncertain cases. In case of prenatal diagnosis, the prognosis will be defined by the search for associated cerebral or extra-cerebral malformations, chromosomal abnormalities (CGH array) or a pathogenic variant in the MN1 gene.
Genetic counseling
RES cases happen sporadically and are not inherited from parents.
Management and treatment
Management is symptomatic and may include surgical treatment of spasticity (e.g. hamstring release), or hydrocephalus. Neuropsychological assessment should be provided for cases involving intellectual and behavioral impairment.
Prognosis
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 frequent. Syndromic cases of RES have a poor prognosis except Gomez-Lopez-Hernandez syndrome.

                            Last update: 
                            November 2023


                            - Expert reviewer(s): 
                            Pr Sylvie ODENT | ITHACA*


                                * European Reference Network