Rhombencephalosynapsis Diagnosed in Childhood: Clinical and MRI ﬁndings

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EUROPEANJOURNALOFPAEDIATRICNEUROLOGY11 (2007) 35– 38

Official Journal of the European Paediatric Neurology Society

Case Study Rhombencephalosynapsis diagnosed in childhood: Clinical and MRI ﬁndings

Jalel Chemlia,Ã, Mejdi Abrouga, Kalthoum Tlilib, Abdelaziz Harbia aDepartment of Pediatrics, Sahloul Hospital, Sousse 4054, Tunisia bDepartment of Radiology, Sahloul Hospital, 4054 Sousse, Tunisia

article info ABSTRACT

Article history: Rhombencephalosynapsis (RES) is a rare cerebellar malformation of unknown etiology Received 8 August 2006 characterized by vermal agenesis or hypogenesis, fusion of hemispheres and the dentate Received in revised form nuclei. Clinical presentation and prognosis are extremely variable and generally depends 18 September 2006 one the associated supratentorial anomalies. We report the ﬁrst Tunisian case of RES Accepted 23 September 2006 diagnosed by magnetic resonance imaging (MRI) in a 3.5-year-old boy born to consanguineous parents. The child had spastic diplegia, facial dysmorphia, skeletal anomalies and Keywords: normal intellectual development. Additional supratentorial anomalies were agenesis of Cerebellar abnormalities septum pellucidum, moderate hydrocephalus and hypogenesis of corpus callosum. In this Rhombencephalosynapsis paper, the clinical and MRI ﬁndings and possible pathogenesis of this disorder are Vermian agenesis discussed. & Ataxia 2006 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. Hydrocephalus

1. Introduction 2. Case report

Rhombencephalosynapsis (RES) is a rare congenital malfor- A 3.5-year-old boy was admitted for delay of acquirement of the mation of the posterior fossa characterised by hypogenesis or walk. He was the fourth child of a consanguineous couple. He agenesis of the vermis, dorsal fusion of the cerebellar was born by normal delivery after uncontrolled pregnancy. hemispheres, fusion of dentate nuclei and superior cerebellar There was no family history of congenital malformations or peduncles. The condition was firstly described by Obersteiner other notable medical problems. Weight was 11.5 kg (5th in 1914 from autopsy of a 28-year-old man who died by percentile), length 87 cm (o3rd percentile) and head circumfer- suicide. It was named RES by Gross and Hoff in 1959.1 The ence 49 cm (13th percentile). Examination at the time of severity of clinical manifestations and prognosis of RES admission revealed facial dysmorphia (low set ears and depends on the posterior fossa findings and supratentorial- hypertelorism ) and normal intellectual development (normal associated anomalies. In this paper, we report a new case of speech). Neurological examination revealed spastic diplegia, RES diagnosed by MRI in a 3.5-year-old boy with spastic lower limb hyper-reflexia and bilateral sign of Babinski. The diplegia. standing position and walking are not possible that with help.

ÃCorresponding author. Tel.: +216 98570560; fax: +216 73367451. E-mail address: [email protected] (J. Chemli). 1090-3798/$ - see front matter & 2006 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2006.09.007 ARTICLE IN PRESS

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General examination revealed scoliosis and genu valgum. Spinal radiography revealed segmentation anomalies of thor- 3. Discussion acic vertebra in T8 and T9 with mild scoliosis. Ophthalmologic examination showed clear corneas and normal fundi. Cranial We describe a new case of RES diagnosed by MRI in a living magnetic resonance imaging (MRI) showed complete agenesis patient. It is only since 1991 with the advent of MRI, that the 2,3 of the vermis with fusion of the cerebellar hemispheres, fusion diagnosis of RES has been made during life. Prenatal of dentate nuclei and superior cerebellar peduncles, biventri- diagnosis of this malformation by MRI is currently possible 4 cular hydrocephalus, hypogenesis of corpus callosum and and has been made in some cases. To date, about 50 cases agenesis of septum pellucidum (Figs. 1 and 2). The pituitary with RES have been described which approximately 36 cases gland and optic chiasm were normal. No other central nervous diagnosed by MRI. Recently, partial RES was described in two system (CNS) or extra-CNS anomaly was detected and chromo- pediatric patients presenting normal development of the somal analysis revealed normal karyotype of 46, XY. anterior vermis and nodulus, but part of the posterior vermis

Fig. 1 – Axial T2-ﬂair images: (a) midline Fusion of cerebellar hemispheres, fusion of cerebellar peduncles and dentate nuclei. (b) Continuing of folia through entire width of cerebellum and abnormal shape of fourth ventricle.

Fig. 2 – Coronal T2-weighted images: (a) Abnormal transverse cerebellar folial orientation. (b) Fusion of the cerebellar hemispheres without intervening vermis. Note also the ventriculomegaly with absence of the septum pellucidum. ARTICLE IN PRESS

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was deficient.5,6 These observations suggest that RES should abnormalities are consistent with this gestational period. be considered as a malformation with variable degree of However, the pathogenesis of this midline defective mal- severity. formation remains unclear and causative factors are con- Most reports are of pediatric patients, although there are troversial. In the traditional view, RES was considered as an some cases of adult subjects in the literature.7,8 Sener9 abnormal development of the vermis with subsequent fusion reported that the frequency of RES was 0.13% in a series of of the hemispheres. In the more recent view, Utsunomiya 3000 pediatric patients who underwent head MRI. Almost et al.16 suggested that fused cerebellar hemispheres may be totality published cases have been sporadic. In our case, there explained by the fact that the cerebellar primordium is was not familial history of malformation and chromosomal essentially unpaired and not a pair of unconnected bilateral analysis was normal but parental consanguinity could structure and concluded that fusion of the cerebellar hemi- suggest an autosomal recessive inheritance. However, con- sphere is not secondary to a primary maldeveloppement of sanguinity is a common constellation in our country. In two the vermis, but rather result from a primary failure of additional cases described in the literature, parents have also vermian differentiation. These authors suggested that this an ethnic background with common constellation of con- cerebellar malformation is due to undivided hemispheres sanguinity.8,10 As no occurrence in sibs was ever observed, an instead of fused hemispheres. However, the hypothesis autosomal recessive inheritance seems very unlikely. of genetic defects remains an interesting research track. Additional abnormalities reported in association with RES In one case, it was reported an anomaly affecting chromo- are variable. Hydrocephalus or ventriculomegaly, dysgenesis some 2q.17 Also, experimental studies on the genetic control of the corpus callosum and absence of the septum pellucidum of early regional specification of brain structures have are the most commonly associated anomaly.8 Fused thalami, identified a critical organizing center for cerebellar develop- tectum and fornices, hypoplasia of the temporal lobes, olivary ment, the ‘‘isthmic organizer’’ located at the junction between nuclei, anterior commissure and optic chiasma and agenesis the mesencephalon and metencephalon and defined by of the posterior lobe of the pituitary can occasionally be seen. caudal and rostral limits of expression of the homeo- Extracranial anomalies are very rare and may involve box-containing genes Otx2 and Gx2, respectively.18 Sarnat19 musculoskeletal, urinary tract, cardiovascular and respiratory suggested that RES is probably due to an underexpression systems.11,12 In our case, there were supratentorial anomalies of a dorsalizing organizer gene. A possible animal model is (agenesis of septum pellucidum, moderate hydrocephalus the Dreher Lmx1a gene mutant mousse which shows agenesis and hypogenesis of corpus callosum) with skeletal abnorm- of the vermis with fusion of the cerebellar hemispheres and alities (spinal segmentation anomalies with mild scoliosis inferior colliculi due to dorsal patterning defects in the and genu valgum) exceptionally described in association with hindbrain, closely resembling human RES.20,21 Lmx1a gene RES. However, musculoskeletal system seems to be the mapping to 1q21–q23 regulate early developmental events at commonest site of associated anomalies in cases with RES. the pontomesencephalic junction. Molecular analysis may Clinical presentation and prognosis are extremely variable reveal a mutation in the Lmx1a gene22 unique to RES. Lmx1a and generally depends one the associated supratentorial was also shown to regulate formation of the roof plate and anomalies. Therefore, no correlation between MRI findings specification of dorsal cell fates in the spinal cord and and clinical manifestations can be established. RES may be developing vertebra.21 So, mutation in the Lmx1a gene could isolated and diagnosed incidentally in adulthood.3,13 Symp- explain spinal abnormalities associated with RES. Further toms of severely affected children include mental retardation, study may reveal other candidate defective genes in RES. spasticity and epilepsy. Delayed cognitive and mental retar- In conclusion, clinical presentation of RES is extremely dation were reported in the majority of the case reports. variable and spastic diplegia may reveal this malformation in Children with isolated RES may have normal cognitive and children. RES diagnosed in childhood are more often asso- language function, at least in early school age.8 Adults with RES ciated with supratentorial than extracranial anomalies. The and no intellectual disability have been reported.13,14 Therefore, cause of RES is unknown; however, hypothesis of genetic in our case, we observed normal cognitive development, defects remains possible. Further study and speculation of previously reported in some pediatric and adult patients8,13 candidate defective genes may shed light on the pathogenesis and spastic diplegia which has been exceptionally described. of this rare cerebellar malformation. However, a long term neurodevelopmental followup is neces- sary to establish intellectual capacity. Non-specific dysmorphic REFERENCES features such as low set ears, hypertelorism and high arched palate were reported by several authors.2,8,10 Involuntary lateral movements (head rolling) without or with only mild cognitive 1. Gross H, Hoff H. Sur les dysraphies craˆnioce´phaliques. In: delay11,15 are reported by several recent papers. Heuyer G, Feld M, Gruner J, editors. 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