Rhombencephalosynapsis and related anomalies: a neuropathological study of 40 fetal cases

Abstract

Rhombencephalosynapsis is an uncommon cerebellar malformation deWned by vermian agenesis with fusion of the hemispheres and of the dentate nuclei. Embryologic and genetic mechanisms are still unknown, and to date, no animal models are available. Ultrasound diagnosis is generally suspected after 22 weeks of gestation, and usually the abnormality is suggested by ventriculomegaly. Morphological analysis of 40 fetuses after medical termination of pregnancy allowed us to conWrm that rhombencephalosynapsis was always associated with other brain abnormalities or malformations: Purkinje cell heterotopias, fusion of colliculi, forking and/or atresia of the aqueduct and of the third ventricle resulting in a fusion of the thalami, agenesis of the corpus callosum, lobar holoprosencephaly and neural tube defects. Pons and medulla were very infrequently abnormal. Furthermore, complete autopsy made it possible to separate either pure neurologic phenotypes, or associated with extraneural anomalies from syndromic forms: Gomez-Lopez-Hernandez syndrome (1 case) and VACTERL-H syndrome (6 cases). The number of our fetal cases strongly suggests that VACTERL-H association related with rhombencephalosynapsis emerges as a non-random association. Furthermore, recurrence and consanguinity were noted in two diVerent families, which argue for a sporadic or inherited cause. From our results, it could be suggested that rhombencephalosynapsis may be due to defective genes regulating formation of the roof plate and the development of midline cerebellar primordium at the junction of the mesencephalon and of the Wrst rhombomere.

Array-CGH Analysis Suggests Genetic Heterogeneity in Rhombencephalosynapsis

“…Magnetic resonance imaging (MRI) of a series of 3,000 consecutive paediatric brains led to its frequency being estimated at 0.13% [Sener, 2000]. However, the systematic use of MRI in the prenatal period suggests that the frequency of RS may be much higher: we have observed 40 foetal cases over 15 years [Pasquier et al, 2009]. Ishak et al [2012] identified RS in almost 10% of patients with aqueductal stenosis, indicating that RS is more common than previously thought.…”

“…Complete autopsy allows pure neurological phenotypes and those associated with extraneural anomalies to be distinguished from syndromic forms: Gomez-Lopez-Hernandez (GLH) syndrome (MIM 601853) [Lopez-Hernandez, 1982;Poretti et al, 2008] and VACTERL-H syndrome (MIM 276950) [Michaud et al, 1982;Pasquier et al, 2009]. In foetal cases, isolated RS without fusion of the colliculi (also named mesencephalosynapsis) or aqueductal anomalies are never observed; various associated supratentorial abnormalities, such as agenesis of the corpus callosum, atresia of the third ventricle and holoprosencephaly, have been described [Pasquier et al, 2009;Mercier et al, 2011;Ishak et al, 2012]. In the postnatal period, there is impaired neurological function in most cases [Romanengo et al, 1997;Danon et al, 2000], although in some cases of RS cognitive functions are normal [Obersteiner, 1914;Bell et al, 2005;Poretti et al, 2009].…”

Rhombencephalosynapsis with and without associated malformations

“…Since in the Wrst case of RES, reported by Obersteiner [2], no clinical data, general autopsy Wndings, nor exact data of the skull and brain are available, it cannot be further evaluated. Although no genetic examinations had been performed in our cases, together with those reported by Pasquier et al [3], they suggest that the frequent combination of both telencephalic and hindbrain malformations in patients with RES may be due to disordered formation of the roof plate and development of midline cerebellar primordia at the junction of the mesencephalon and the Wrst rhombomere.…”

“…Pasquier et al [3], in a recent morphological analysis of 40 fetuses from 14 to 35 weeks of gestation found rhombencephalosynapsis (RES) in 11 cases and diencephalo-mesencephalosynapsis in 24 cases, usually associated with other brain anomalies or malformations (agenesis or hypoplasia of corpus callosum, lobar holoprosencephaly, encephalocele, stenosis or forking of Sylvian aqueduct, ventricular dilatation; and extraneuronal anomalies, e.g., VACTERL + H syndrome, etc), while in only two cases of RES (#9, #11) no additional abnormalities were observed. Thus, separation between pure neurological phenotypes and those associated with other syndrome-anomalies were possible.…”

Clinical Features and Outcomes of Holoprosencephaly in Korea

“…Because the midbrain is often involved in holoprosencephaly, aqueductal stenosis or even atresia, resulting in obstructive hydrocephalus, can be superimposed on the basic malformation of the forebrain. In addition, posterior fossa abnormalities such as rhombencephalosynapsis, in which abnormal nonseparation of the cerebellar hemispheres occurs, are also occasionally observed in holoprosencephaly [29][30][31].…”