Hemimegalencephaly is a rare central nervous system disorder of neuronal cell lineage, proliferation, maturation, and migration characterized by in utero
Aug. 24, 2021
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In this article, the author defines a congenital malformation of agenesis of the vermis with fusion of, rather than subarachnoid space between, the cerebellar hemispheres. The dentate nuclei also are fused. This dysgenesis may be isolated or associated with other cerebral malformations, including holoprosencephaly and Chiari malformations, aqueductal stenosis, and chromosomopathies. Clinical, imaging, and neuropathological features are defined, though the clinical picture is variable. The diagnosis may be established prenatally by fetal neuroimaging. It does not cause obstructive hydrocephalus unless associated with Chiari malformations, aqueductal stenosis, or X-linked hydrocephalus; no treatment is available or required unless obstructive hydrocephalus is a complication.
• This malformation is characterized by congenital absence of the vermis with fusion of the medial sides of the cerebellar hemispheres and of the dentate nuclei, unlike subarachnoid space in the cerebellar midline as in Joubert syndrome and Dandy-Walker malformation.
• The malformation may be isolated or associated with other malformations, particularly dorsal midline defects such as noncleavage of the tectal plate of the midbrain, septo-optic dysplasia, holoprosencephaly, aqueductal stenosis, Chiari malformations, and occasionally, agenesis of the corpus callosum.
• The syndrome is described in a variety of chromosomopathies and other genetic defects but also occurs without an evident genetic etiology.
• Isolated rhombencephalosynapsis does not cause obstructive hydrocephalus or require treatment, but is frequently associated with aqueductal stenosis, including X-linked hydrocephalus and, occasionally, Chiari malformations.
• The diagnosis can be established prenatally by fetal ultrasound or fetal MRI.
Absence of the vermis with fusion of the cerebellar hemispheres was first described in 1914 by Obersteiner from an autopsy of a 28-year-old man who committed suicide (72). The term “rhombencephalosynapsis” was coined in 1959 by Gross and Gross and Hoff (35; 35). The association of some cases with septo-optic-pituitary dysplasia also was first demonstrated by Gross and Hoff and has been confirmed neuropathologically by several other authors (35; 68; 88; 94; 04).
As with all cerebellar vermal defects in development, gross motor developmental delay, generalized muscular hypotonia, truncal titubation, and, later, ataxia are the most constant manifestations (55). Horizontal and vertical phasic nystagmus may be present, but cranial neuropathies and other brainstem lesions are absent. If forebrain structures are involved, as with septo-optic-pituitary dysplasia, cognitive and intellectual functions may be affected. Pituitary insufficiency may range from isolated growth hormone deficiency to diabetes insipidus to panhypopituitarism.
Rhombencephalosynapsis may be an isolated anomaly (75) or may be associated with other malformations not only of the CNS but also of multiple organ systems and the extremities (47). A high incidence of children with rhombencephalosynapsis exhibit additional congenital anomalies of the hands, including syndactyly, preaxial polydactyly, phalangeal hypoplasia, and absence or duplication of the thumb (08; 104; 70; 77; 107). Contractures of the elbows (104) and limb reduction syndromes also are associated (107). Single umbilical artery occurs occasionally in the absence of abnormal chromosomal karyotype (48). Rhombencephalosynapsis is associated with the VACTERL syndrome (vertebral anomalies, anal atresia, cardiovascular anomalies, tracheoesophageal fistula, renal anomalies, and limb defects) (44).
An association with X-linked obstructive hydrocephalus, usually with aqueductal stenosis, due to L1-CAM gene mutations at locus Xq28, is documented; 27% of 57 cases had rhombencephalosynapsis as 1 component (04). The association of rhombencephalosynapsis with other forms of aqueductal stenosis is high, and the resulting hydrocephalus is an important determinant factor in neonatal outcome, motor impairments, and developmental delay (50).
The Gómez-López-Hernández syndrome, described from Mexico but also found in other ethnic groups, is a specific genetic form of rhombencephalosynapsis (60; 116; 127; 17; 82; 31; 112; 23; 22; 32). It consists of rhombencephalosynapsis, atresia of the 4th ventricle, bilateral parietal or parieto-occipital alopecia, and trigeminal anesthesia that often gives rise to corneal opacities. MRI features are characteristic. They also may include variable supratentorial anomalies such as agenesis of the septum pellucidum and generalized ventriculomegaly (51). The trigeminal nerve agenesis or dysfunction component is the most variable and may not be present in all cases; facial dysmorphism and ataxia also are inconstant features not required to meet the diagnostic criteria (112; 23). Rare cases have associated aqueductal stenosis, resulting in obstructive hydrocephalus diagnosed prenatally (32). Craniosynostosis was reported in the original case (60) but not in others. The variable-associated features suggest an underlying spectrum rather than a collection of unrelated discrete syndromes (119). Autism spectrum disorder occurs in some children (54). Proposed obligatory diagnostic criteria include rhombencephalosynapsis, biparietal scalp alopecia, trigeminal anesthesia, and 1 of 2 major craniofacial dysplasias of brachycephaly or turricephaly, the latter being midfacial hypoplasia (90; 09). Facial dysmorphisms also can include hypertelorism and low-set and posteriorly rotated ears (09). The syndrome occurs in both genders. All ethnic populations may be affected; the first Japanese patient was reported (51). The exact genetic mutation is not yet known.
Incomplete forms of midline cerebellar fusion are described as “partial rhombencephalosynapsis” (53; 87). Other malformations of the brain also occur in association with rhombencephalosynapsis, involving not only the cerebellum and brainstem, but also supratentorial structures. Septo-optic-pituitary dysplasia is the most frequent association, but other cerebral malformations include abnormal gyration and even lissencephaly, subcortical heterotopia, partial callosal agenesis, absence of the septum pellucidum, and noncleavage of the thalami (110; 77; 21). Malformations of brainstem structures, such as the inferior olivary nuclei, which is part of the cerebellar system, also are frequent; the fastigial, as well as the dentate, cerebellar nuclei may be fused in the midline (46). The association with other dorsal midline defects in brain development is frequent: septo-optic dysplasia has already been mentioned, but agenesis of the corpus callosum and noncleavage of the tectal (collicular) plate of the midbrain also are reported (06; 115; 12). Despite the fusion of the medial walls of the cerebellar hemispheres instead of leaving a subarachnoid space in place of the vermis as in Dandy-Walker malformation, some cases show an expanded fourth ventricle forming a Dandy-Walker cyst (83; 102). Severe forebrain anomalies, including aprosencephaly, with rhombencephalosynapsis are documented in rare cases (115). Chiari malformations are not usually associated with rhombencephalosynapsis, but MRI appearances can be misleading (39), and rare cases of this true association are reported (66).
Rhombencephalosynapsis is one of several cerebral anomalies forming a syndrome of severe micrencephaly, abnormal or absent gyration/sulcation of the cerebral cortex, agenesis of the corpus callosum, and tethered spinal cord with scoliosis. The genetic etiology in some of these extreme cases is mutation in a zinc finger protein of cerebellum 1 (122) or a variant of the ADGRL2 gene (124). Pontocerebellar hypoplasia type 1B includes rhombencephalosynapsis and microlissencephaly and is associated with EXOSC3 gene mutation (97).
Visceral anomalies of the cardiovascular, respiratory, and urinary tract systems are rare but do occur in some patients (24; 73; 30; 05). Facial dysmorphism occurs in a minority as a midfacial hypoplasia with hypotelorism, but never is as severe as in holoprosencephaly (59; 107); most of these cases probably have septo-optic-pituitary dysplasia. Other minor facial dysmorphisms include frontal bossing, flattened midface, ear anomalies, and hypertelorism (05).
Neurologic function referable to the cerebral cortex depends on normal or abnormal cortical development. In some cases of isolated rhombencephalosynapsis or that associated with mild forebrain dysgeneses, intelligence may be normal in children and adults (117; 14; 21). In other cases with variable abnormalities of cortical convolutions and of microscopic laminar architecture, there may be cognitive and learning disabilities or frank mental retardation. Epilepsy is not a common complication, but may occur secondary to cerebral cortical dysplasias. Spastic diplegia may occur, but it is not characteristic. Visual impairment may be a complication, particularly if optic nerve hypoplasia is present in rhombencephalosynapsis associated with septo-optic dysplasia (111). Delayed visual attention processing in rhombencephalosynapsis suggests a supplementary role of the vermis in visual responsiveness independent of eye movements (67). Strabismus, particularly esotropia, may be a presenting sign with or without amblyopia (19). Optic coloboma and agenesis of the trigeminal ganglion has been interpreted as a variant of cerebello-trigeminal dermal dysplasia (113). Torticollis with craniosynostosis of the sagittal suture (scaphocephaly) and cerebellar signs are associated rarely (52). Head-shaking stereotypies may be a diagnostic clue. In 1 series, 37 of 45 infants and children with rhombencephalosynapsis exhibited this clinical sign, and persistent figure-8 and side-to-side head shaking is almost pathognomonic (119; 120).
Because the malformation does not usually obstruct the fourth ventricle and aqueductal stenosis/atresia are associated findings in a minority of cases, secondary obstructive hydrocephalus is not an invariable complication. Nevertheless, some cases do have generalized ventriculomegaly (68; 117; 21), and massive hydrocephalus occurs rarely (46; 130). Associated aqueductal stenosis with fetal hydrocephalus was reported at 23 weeks’ gestation and in many prenatal MRI studies at more advanced gestational ages (104).
Clinical signs that form a basis for neuroimaging are truncal titubation and delayed gross motor skills in infants and ataxia in older children. The facial dysmorphism, head shape, and biparietal alopecia are strong clinical indicators. A minority of patients have epilepsy, and seizures may even appear in early infancy (105). Stereotypical head shaking is described in some infants with rhombencephalosynapsis (03). The presentation of cognitive deficits, stereotypies, and seizures indicate that the malformation is not limited to the cerebellum but also involves some supratentorial structures as well.
Cognitive outcomes of children with rhombencephalosynapsis depend in part on other brain anomalies, obstructive hydrocephalus for aqueductal stenosis, and the association with genetic syndromes. Apart from these factors, the outcome is still variable in apparently “isolated” cases: in a study, only 2 of 5 children had an IQ within the normal range, and hyperkinesis and other behavioral disorders were frequent (81). Some patients exhibit a self-mutilating behavior (123).
This malformation is not progressive, but the child will always have ataxia and other cerebellar deficits, often along with developmental delay of gross motor skills, in particular (74; 80). Intelligence may or may not be affected, depending on associated malformations. Epilepsy and hydrocephalus are not usually complications, but are treatable. Pituitary insufficiency is another treatable complication in some cases. Hydrocephalus due to associated aqueductal stenosis may be diagnosed prenatally by ultrasound and MRI fetal imaging and may indicate preterm delivery to initiate surgical treatment of the hydrocephalus in the neonatal period. The degree of hydrocephalus, particularly in those cases associated with aqueductal stenosis, and its early treatment, is an additional determinant factor in the prognosis of motor deficits and cognitive/intellectual function.
Rhombencephalosynapsis is not known to be due to acquired lesions of the fetal brain, vascular, physical, or metabolic. The association with other malformations of the brain and spinal cord, particularly midline dysgeneses, and with defective development of the limbs in some cases, is strong evidence in favor of a genetic pathogenesis. The timing of the initiation of the malformation is probably about 4 to 5 weeks’ gestation, before the actual development of the cerebellum from the rhombic lip of His. It is probably a gene mutation in a gene of the dorsoventral gradient of the vertical axis of the rostral hindbrain (see Pathogenesis and pathophysiology section below).
Most cases of rhombencephalosynapsis are sporadic and are not transmitted as a Mendelian trait, but occasional families of autosomal recessive inheritance are reported (89). Autosomal dominant polycystic kidneys may include rhombencephalosynapsis as an additional anomaly (30). Cytogenetic studies usually show a normal karyotype (100). An unbalanced subtelomeric translocation t(2p; 10q) was discovered by fluorescent in situ hybridization in a fetus (59). An infant with severe malformations of multiple organs and rhombencephalosynapsis had an isochromosome 9p nonmosaic tetrasomy (28). A genetic basis for rhombencephalosynapsis remains unknown in the majority of cases despite intensive genetic screening (05).
Rhombencephalosynapsis is a midline defect in CNS development, and is associated with other midline defects such as agenesis of the septum pellucidum and hypoplasia or absence of the corpus callosum. It is probably a defect in the molecular genetic programming of the nervous system, most likely downregulation of a gene that acts in the dorsoventral gradient of the vertical axis of the neural tube, such as 1 of the BMP or PAX families (95; 93). This mechanism also could explain the fusion of the medial sides of the cerebellar hemispheres and dentate nuclei, analogous to the noncleavage of the forebrain and diencephalon in holoprosencephaly. Indeed, partial rhombencephalosynapsis was reported in association with holoprosencephaly in siblings who both had a mutation of ZIC2 (87). However, some authors deny that ZIC2 occurs in partial rhombencephalosynapsis in the absence of holoprosencephaly (37). Similarly, and probably for the same reason of faulty genetic gradients, stenosis or atresia of the midbrain cerebral aqueduct is a frequent accompanying lesion with rhombencephalosynapsis and is a principal cause of obstructive hydrocephalus beginning in fetal life or early infancy (49; 43; 32). MN1 C-terminal truncation syndrome includes craniofacial anomalies and incomplete rhombencephalosynapsis (62).
The specific dorsalizing developmental gene has not been identified, but the PAX and BMP families are suspected. Mutations of genes at the mesencephalic-metencephalic junction of the early neural tube (the “isthmic organizer”), such as LMX1a, also are suggested (46; 130). The Dreher LMX1a genetic mutant mouse has agenesis of the vermis with fusion of the cerebellar hemispheres and inferior colliculi as a dorsal patterning defect of the hindbrain, and these mice also have anomalies of the limbs (63; 69). Defective expression of other genes at this junction, such as WNT1, EN1, and EN2, cause agenesis of the midbrain and metencephalon with global cerebellar aplasia or hypoplasia in the mouse and human, but not rhombencephalosynapsis (96). Some authors attribute the defect to genes regulating the formation of the roof plate and midline cerebellar primordial at the junction of the mesencephalon and at rhombomere 1 (76); this interpretation is entirely consistent with the concept of downregulation of a dorsalizing gene in the vertical axis at the level of the mesencephalon and rostral rhombomeres, and it also explains noncleavage of the collicular plate and aqueductal stenosis in some cases. Agilent oligonucleotide arrays in 57 patients with rhombencephalosynapsis yielded results of genetic heterogeneity, with 4 different unbalanced rearrangements: 16p11.2 deletion, 14q12q21.2 deletion, unbalanced translocation of t(2p; 10q), and 16p13.11 microdeletion containing 2 candidate genes (27).
Segmentation of the embryonic neural tube is another important developmental process that may be altered in the pathogenesis of rhombencephalosynapsis. The finding of incomplete separation of midbrain and forebrain in cases of rhombencephalosynapsis suggest that defective segmentation is an associated mechanism (115; 44).
Rhombencephalosynapsis is not due to vascular lesions, ischemia, or infarction of the fetal cerebellum. Fetal and postnatal neuropathological studies both confirm the neuroimaging diagnosis and demonstrate the fusion of the cerebellar hemispheres and dentate nuclei in the absence of a vermis, as well as other associated midline dorsal malformations of the brain; these include aqueductal stenosis, noncleavage of the collicular plate, agenesis of the septum pellucidum, hypoplasia of the corpus callosum, and sometimes other supratentorial anomalies (11; 76). The association of rhombencephalosynapsis with aqueductal stenosis is particularly strong (128). Of 12 cases of fetal arachnoidal cysts diagnosed prenatally by ultrasound or MRI at a mean gestational age of 28 weeks, 1 also exhibited rhombencephalosynapsis (25). Three of these 12 cysts were in the posterior fossa.
This is a rare malformation, but the true incidence is unknown. It was estimated to have a frequency of 0.13% (100), but from the number of cases reported, it is probably more common (46).
No means of prevention is known. It can be diagnosed in utero at midgestation by neuroimaging.
Rhombencephalosynapsis must be distinguished from other disorders of development of the cerebellar vermis: Dandy-Walker malformation and Joubert syndrome are the principal differential diagnoses, but these are excluded by the demonstration of a fluid-filled space in the site of the vermis and by the cystic posterior expansion of the fourth ventricle in the case of Dandy-Walker malformation (114; 15; 101). The diagnosis can be established prenatally by fetal MRI in both completely expressed and partial forms (29; 53; 106). In a midgestation fetus, absence of the vermis with fusion of the medial walls of the cerebellar hemispheres (rhombencephalosynapsis) was present, but also a large Dandy-Walker posterior fossa cyst (104). The imaging distinction between simple rhombencephalosynapsis and the Gómez-López-Hernández syndrome must be made; a bipartite parietal bone sometimes is a clue (02).
In a young male adult with rhombencephalosynapsis, a Chiari II malformation coexisted, as well as a cervicothoracic meningomyelocele, diastematomyelia, and a tethered spinal cord (103). Partial rhombencephalosynapsis and Chiari II malformations were described in another case (125). In a larger series, 5 of 9 pediatric cases of rhombencephalosynapsis had Chiari malformations, types 1 or 2, which were associated with symptomatic obstructive hydrocephalus Weaver et al 2013). At times atypical cases of Chiari II malformation may merely mimic partial rhombencephalosynapsis (38). A syndrome in which only the posterior vermis is congenitally absent has been demonstrated in fetal brains (91). At times, rhombencephalosynapsis may be “partial,” with absence of the posterior vermis and fusion in the inferior part of the cerebellum (114; 26; 125; 53). Midline cerebellar tumors might be an initial consideration, but rhombencephalosynapsis is not a mass lesion, does not obstruct the fourth ventricle, and usually is easily distinguished from neoplastic lesions.
Imaging, particularly MRI, is the best means of demonstrating this malformation in the living patient, and the MRI appearance is characteristic and diagnostic at or before birth (98; 118; 109; 34; 121; 10; 24; 70; 99; 100; 73; 79; 108; 117; 15; 26; 65; 110; 56; 21; 85; 20; 25; 45; Kobayahshi et al 2015; 84; 01; 07; Poretti et al. 2016). Atypical cases with cerebellar agenesis limited to the anterior vermis are described (45).
Rhombencephalosynapsis is being diagnosed prenatally with increasing frequency by fetal ultrasound in the second trimester and MRI, which demonstrate not only the fusion of the cerebellar hemispheres with absence of the vermis, but also the enlargement of the lateral and third ventricles, distortion of the fourth ventricle, and sometimes aqueductal stenosis or atresia, confirmed neuropathologically (71; 17; 64; 76; 13; 18; 45; 84; 07; 86; 43; 58; 41; 42; 78). Occasionally, it can even be diagnosed ultrasonographically during the first trimester screening if accompanied by aqueductal stenosis (61). On the other hand, some cases are not diagnosed until adult life (40; 65; 16). Axial, coronal, and sagittal planes of MRI examination are all diagnostic. The “molar tooth sign,” closely associated with Joubert syndrome, also may be present in rhombencephalosynapsis (15). Because of the association with septo-optic-pituitary dysplasia, midline structures of the forebrain should also be carefully examined and special view of the optic nerves should be requested for the MRI. Diffusion tensor imaging is useful in further distinguishing rhombencephalosynapsis from Joubert syndrome (129). A rare variant of rhombencephalosynapsis with fusion of the cerebellar hemispheres ventral, rather than dorsal, to the brainstem has been demonstrated in a 17-month-old boy by MRI (92). Prenatal diagnosis is now available and rhombencephalosynapsis has been diagnosed by fetal MRI at 27 and 32 weeks’ gestation in one of dizygotic twins, confirmed by postnatal MRI (53), and also in other cases by fetal MRI (33; 106). Prenatal 3D-MPR images of the fetal posterior fossa are also now possible to facilitate the diagnosis of rhombencephalosynapsis (57).
Diffusion tensor imaging (DTI) has only been applied and assisted in documenting partial rhombencephalosynapsis associated with Chiari II malformation (66).
Ophthalmological examination and endocrine studies should be considered. The hands should be carefully examined and roentgenograms taken if any suggestion of distal appendicular dysgenesis should be evident by physical examination. Chromosomal karyotype and metabolic studies are nearly always normal, but in cases associated with septo-optic-pituitary dysplasia, endocrine abnormalities of growth hormone or panhypopituitarism may be found in some.
Hypothalamic-pituitary insufficiencies should be identified and replacement therapy given. If hydrocephalus is a complication, usually in cases associated with Chiari malformations or with holoprosencephaly, shunting may be required; some cases may require foramen magnum decompression (126). In isolated rhombencephalosynapsis, obstructive hydrocephalus is usually not a complication. Physiotherapy, with emphasis on gait training, should be undertaken, appropriate to the age of the child.
Harvey B Sarnat MD FRCPC MS
Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.See Profile
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