Rhombencephalosynapsis

Rhombencephalosynapsis (RES) is a developmental defect of the cerebellum characterized by a partial to complete absence of the cerebellar vermis and fusion of the cerebellar hemispheres, dentate nucleus and the middle peduncles. The diagnosis of RES requires identification of these key characteristics in post and pre-natal neuroimaging. 

No specific code for RES in ICD 9 or 10

RES is very rare and the prevalence is unknown. However, in a post-natal study of 3,000 pediatric patients, the incidence was 0.13% ¹ 

The most accepted theory for this cerebellar anomaly suggests that a disturbance to cerebellar development occurs at approximately 33–34 days of gestation due to abnormal isthmic organizer formation. The isthmic organizer is a critical organizing center for the midbrain and hindbrain (MB-HB) structures and is located at the junction of the mesencephalon and metencephalon in the early embryo. Abnormal positioning of the isthmic organizer results in the formation of abnormal and/or rudimentary MB-HB structures ². Dorsal–ventral patterning defects may result in a loss of the midline and fusion of lateral structures leading to RES³. Another theory defends the loss of the anterior cerebellar anlage cells, meant to give origin to the vermis, and cerebellar fusion somewhat parallel to the mechanism of holoprosencephaly in the forebrain⁴. This possible, yet unclear, shared pathophysiology is the probable reason as to why both these anomalies are seen simultaneously in some patients with ZIC2 mutations⁵. Until now, no genetic cause (single gene) of RES has been consistently defined. In familial recurrent cases, an autosomal recessive pattern is suggested⁶. RES is also a feature of non-recurrent chromosomal aberrations. Nevertheless, the majority of cases, including Gomez-Lopez-Hernandez syndrome, are de novo autosomal dominant mutations⁶.

RES can be complete or partial, according to the severity of the vermian agenesis⁷. Complete RES can often be detected during the second trimester of pregnancy using ultrasound, due to more severe presentation and associated findings. Partial RES occurs when only part(s) of the vermis is/are missing and only the nodulus, the posterior vermis or the anterior vermis are present. Prenatal detection of partial RES poses a diagnostic challenge, as the transverse cerebellar diameter (TCD) can be completely normal for the gestational age, without other abnormalities. The partial juxtaposition of the hemispheres makes for very difficult interpretation of the midline images using ultrasound. Fetal brain MRI may be of help during the third trimester, but the spatial resolution is by far lower than the optimum to allow for correct classification in some cases, when compared to postnatal imaging. 
A small transcerebellar diameter (TCD) is usually the main finding to raise suspicion of RES⁷. The presence of ventriculomegaly in the early second trimester also demands a dedicated assessment of the fetal midbrain-hindbrain structures in order to rule out RES, as the occurrence of aqueductal stenosis secondary to a midbrain malformation is quite frequent.
 
CEREBELLAR FINDINGS: 
- Small TCD (<10th centile); 
- Round shaped posterior cerebellum in axial and coronal views: the effacement of the posterior cerebellar notch/vallecula cerebelli due to the absent vermis and fusion of the hemispheres; This finding is more severe in complete cases with severe cerebellar hypoplasia. 
- Absence of the hyperechogenicity between the cerebellar hemispheres: the vermis is significantly more echogenic than the parenchyma of the hemispheres due to its fern-like structure with deep fissures. 
- Abnormally continuous folia between hemispheres 
- Abnormal 4th ventricle (4v) morphology in all planes: In axial planes the 4v may be completely obliterated, round shaped with small dimensions, key-hole shaped. In sagittal views the common presentation in complete RES is a C-shaped 4v, in which no fastigial point is visible. Very small dimensions or complete obliteration may be also observed. When the vermis is not completely absent, the midsagittal view may assume different aspects, depending on the configuration. 
- Midsagittal views of the cerebellum in complete RES depict cerebellar hemisphere tissue instead of the vermis. The differential diagnosis between the vermis and fused hemispheres is based on the folia indentations, which are quite more shallow than the vermian fissures. 
- Cerebellar ectopy (superior or inferior) 
- MRI studies clearly depict the fusion of the dentate nucleus in T2-weighted axial and coronal views. The dentate fusion may be of various degrees and its shape varies accordingly.

BRAINSTEM FINDINGS: (not mandatory) 
- Pontine hypoplasia 
- Enlarged and thickened tectum 
- Aqueductal stenosis 
- Thickened and fused superior cerebellar peduncles 

SUPRATENTORIAL FINDINGS: (not mandatory) 
- Symmetric ventriculomegaly (often severe – hydrocephalus) 
- Callosal agenesis (partial / complete) / dysgenesis 
- Abnormal gyration and cortical development (secondary to early hydrocephalus) 
- Agenesis of the septi pellucidi 

RES can be seen isolated or in association with extra-CNS anomalies such as VACTERL (‘Vertebral anomalies, Anal atresia, Cardiovascular anomalies, Trachea-Esophageal fistula, Renal anomalies, Limb defects’), holoprosencephaly (HPE) and Gómez-Lopez-Hernández (GLH) Syndrome^{7, 8} (7). The final diagnosis of GLH may be established only postnatally and includes the association of RES with trigeminal anesthesia, bilateral parieto-occipital alopecia, craniosynostosis and craniofacial anomalies⁹.

The differential diagnosis of cerebellar hypoplasia is quite wide, although in most cases there is an abnormal communication between the cisterna magna and the 4v due to vermian dysgenesis. In RES, this feature never occurs and the differential diagnosis lies in entities in which the vermis is absent or very hypoplastic and the hemispheres are juxtaposed or compressed, but not fused. RES imaging findings can be confused with Chiari II malformation which may present with a hard-to-examine, deformed vermis due to compression of the structure upon herniation through the foramen magnum¹⁰. RES and Chiari II malformation also have common extra-cerebellar imaging findings including ventriculomegaly and aqueductal stenosis. The presence of a neural tube defect may also be found in both cases (RES-VACTERL association). A Chiari II malformation can be differentiated from RES by identifying a cerebellar herniation, a “tube-like” rounding of the 4th ventricle, tectal beaking and a normal nodulus¹⁰. Joubert syndrome (JS), with completely absent or severely hypoplastic vermis and juxtaposed hemispheres,  is another differential diagnosis. In JS, the molar tooth sign may be observer either by US or MRI, however the association with hydrocephalus is infrequent and the TCD is usually within the normal range in the vast majority of cases. Regarding genetic studies, no single gene is clearly pointed to be in association with pure-RES findings, which is different from other causes of cerebellar hypoplasia.

Clinical manifestations are wide and may vary from mild ataxia to severe symptoms such as swallowing difficulties, delayed motor acquisitions, muscular hypotonia, spastic quadriparesis, cerebellar signs including dysarthria, cognitive impairment, abnormal eye movements, nystagmus, seizures and hydrocephalus¹¹. The clinical prognosis of RES is dependent on the severity of these manifestations. 

There are no clinical studies that have systematically assessed the prognosis of RES regarding prenatal imaging features. Ishak et al published the results for the neurodevelopmental outcome of 37 patients diagnosed postnatally⁶. Clinical outcome was poorer in RES associated with forebrain anomalies and VACTERL features and less severe in GLH and isolated cases. Subjects with complete vermian agenesis, severe ventriculomegaly, aqueductal stenosis and abnormal temporal cortex also had poorer scores. 

There is no treatment available for either pre- or postnatally diagnosed for RES. Aqueductal stenosis and severe ventriculomegaly may be treated with neurosurgery (third ventriculostomy/VP-shunting) whenever indicated. In countries and circumstances in which termination of pregnancy is allowed, it should be discussed with the parents, especially in cases featuring poor prognostic features. 
No prevention measures are known currently, as the responsible genes are not identified yet.

1.    Sener RN. Unusual MRI findings in rhombencephalosynapsis. Comput Med Imaging Graph 2000; 24: 277-282.
2.    Haratz KK, Lerman-Sagie T. Prenatal diagnosis of brainstem anomalies. Eur J Paediatr Neurol 2018; 22: 1016-1026.
3.    Sarnat HB, Flores-Sarnat L. Etiological classification of CNS malformations: integration of molecular genetic and morphological criteria. Epileptic Disord 2003; 5 Suppl 2: S35-43.
4.    Pasquier L, Marcorelles P, Loget P, Pelluard F, Carles D, Perez MJ, Bendavid C, de La Rochebrochard C, Ferry M, David V, Odent S, Laquerriere A. Rhombencephalosynapsis and related anomalies: a neuropathological study of 40 fetal cases. Acta Neuropathol 2009; 117: 185-200.
5.    Ramocki MB, Scaglia F, Stankiewicz P, Belmont JW, Jones JY, Clark GD. Recurrent partial rhombencephalosynapsis and holoprosencephaly in siblings with a mutation of ZIC2. Am J Med Genet A 2011; 155A: 1574-1580.
6.    Ishak GE, Dempsey JC, Shaw DW, Tully H, Adam MP, Sanchez-Lara PA, Glass I, Rue TC, Millen KJ, Dobyns WB, Doherty D. Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity. Brain 2012; 135: 1370-1386.
7.    Krajden Haratz K, Oliveira Szejnfeld P, Govindaswamy M, Leibovitz Z, Gindes L, Severino M, Rossi A, Paladini D, Garcia Rodriguez R, Ben-Sira L, Borkowski Tillman T, Gupta R, Lotem G, Raz N, Hamamoto T, Kidron D, Arad A, Birnbaum R, Brussilov M, Pomar L, Vial Y, Leventer RJ, McGillivray G, Fink M, Krzeszowski W, Fernandes Moron A, Lev D, Tamarkin M, Shalev J, Har Toov J, Lerman-Sagie T, Malinger G. Prenatal diagnosis of rhombencephalosynapsis: neuroimaging features and severity of vermian anomaly. Ultrasound Obstet Gynecol 2021; 58: 864-874.
8.    Arisoy R, Erdogdu E, Pekin O, Tugrul S, Aydin H, Yorganci C. A rare case of rhombencephalosynapsis and prenatal diagnosis. J Obstet Gynaecol 2016; 36: 839-841.
9.    McAuliffe F, Chitayat D, Halliday W, Keating S, Shah V, Fink M, Nevo O, Ryan G, Shannon P, Blaser S. Rhombencephalosynapsis: prenatal imaging and autopsy findings. Ultrasound Obstet Gynecol 2008; 31: 542-548.
10.    Guleria S, Kelly TG, Maheshwari M, Segall HD. An Atypical Case of Chiari II Malformation Mimicking Partial Rhombencephalosynapsis. Neuroradiol J 2012; 25: 528-532.
11.    Utsunomiya H, Takano K, Ogasawara T, Hashimoto T, Fukushima T, Okazaki M. Rhombencephalosynapsis: cerebellar embryogenesis. AJNR Am J Neuroradiol 1998; 19: 547-549.

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