The group of brainstem-cerebellar hypoplasia- dysplasia includes a spectrum of developmental disorders from the very rare complete cerebellar agenesis to more common forms of hypoplasia with diffuse brainstem involvement. Figure 7.1 illustrates an example of nearly complete cerebellar agenesis.
Hypoplasias can affect different cerebellar regions.
In addition to motor deficits, children may exhibit diminished levels of intelligence with decreased or borderline IQ values, impairments in executive functioning, language deficits, and psychoaffective disturbances, including autistic-like behavior and obsessive rituals (Courchesne et al.,1994). Cerebellar hypoplasia with endosteal sclerosis is a rare disorder with a probable autosomal recessive transmission (Ozgen et al.,2005). Patients exhibit cerebellar ataxia associated with cerebellar hypoplasia, hypotonia, developmental delay, microcephaly, growth retarda- tion, endosteal sclerosis, tooth eruption disturbances, and hip dislocations.
Chiari malformations represent the most com- mon posterior fossa malformations. They are char- acterized by a downwards displacement of brainstem and cerebellar tonsils through the foramen magnum (Chiari,1891). Type II Chiari malformations are com- plex malformations of the entire neuraxis. Almost all
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Table 7.1 Classification of mid-hindbrain developmental disorders
Malformations of both midbrain and hindbrain Brainstem-cerebellar hypoplasia/dysplasia Chiari type II
Cobblestone lissencephaly
Molar tooth sign–associated malformations (Joubert syndrome and associated disorders)
Rhombencephalosynapsis Malformations affecting mainly the cerebellum and
derivatives (Rhombomere 1) Focal or hemispheric hypoplasia
Paleocerebellar hypoplasia (affecting mainly the vermis; including Dandy-Walker malformation and cerebellar vermis hypoplasias) Neocerebellar hypoplasia
Malformations affecting mainly the lower hindbrain
(Rhombomeres 2–8) Chiari type I
Cranial nerve and nuclear aplasias Developmental abnormalities of posterior fossa Abnormal fluid collections
Abnormal bone and brain structure
Pre-natal onset degeneration Pontocerebellar hypoplasia
Congenital disorders of glycosylation Adapted from: Parisi and Dobyns (2003).
patients have an associated meningomyelocele, most often in the lumbar region (Arnold-Chiari malforma- tion). Clinically, the spectrum of symptoms is large.
Patients may be nearly asymptomatic or exhibit severe disabilities. Respiratory failure, swallowing difficulties, and vocal cord dysfunction due to brainstem involve- ment are causes of death. While neonates typically show a rapid neurological deterioration over a period of several days, older patients experience an insidious progression of symptoms. Cerebellar dysplasia may be associated, and there may be a dorsal angulation of the cerebellarfissures (Madsen et al.,2002).The cerebel- lum and brainstem are inferiorly displaced through a wide foramen magnum, leading to compression and impaction of pyramis, uvula, and nodulus. Axial views show an “angel wing” aspect of the brainstem due to prepontine migration of the cerebellum at the level of the middle cerebellar peduncles. Inferior vermian pegs posterior to the medulla is a constant obser- vation (Wolpert et al,,1987).The fourth ventricle is usually collapsed, but may be dilated if trapped.
Mesencephalic abnormalities involving the aqueduct and colliculi are common (Naidich et al.,1980).The tectum may be bulbous or beaked. Aplasia/hypoplasia of cranial nerve nuclei may be found. Defects of the corpus callosum are observed in up to 80% of patients (Barkovich,1995). Complete agenesis occurs in one-third of patients. Supratentorial CSF spaces are commonly prominent. A majority of patients before 6 months of age present a marked thinning of the occipital and parietal bones (craniofenestria). Surgery for the Chiari II malformation is often difficult. Suboc-
cipital craniectomy may be dangerous due to the low position of the torcular. Possible hydrocephalus fol- lowing surgical closure of the myelomeningocele and complications of ventricular shunting such as isolation of the fourth ventricle must be kept in mind. Chiari type III malformation is characterized by a cervico- occipital cephalocele with hindbrain dysplasia. Stig- mata of Chiari type II are commonly found.
Cobblestone lissencephaly with mid-hindbrain abnormalities and cerebellar hypoplasia may be asso- ciated with congenital muscular dystrophy and ocu- lar deficits, including muscle-eye-brain disease and Fukuyama congenital muscular dystrophy (Dobyns &
Truwit,1995).
Molar tooth sign–associated malformations include Joubert syndrome and Joubert syndrome–
related disorders. The estimated prevalence is about 1 per 100 000. Joubert syndrome is characterized by both intrafamilial and interfamilial phenotypic vari- ability, including in monozygotic twins (Raynes et al., 1999). Joubert syndrome has been defined on the basis of clinical findings, including hypotonia, develop- mental delay and mental retardation, abnormal ocular movements, and abnormal breathing with episodes of hyperpnea or apnea, and the presence of the molar tooth sign on cranial MRI (Maria et al.,1999).
This sign includes a deepened interpeduncular fossa, hypoplastic cerebellar vermis, and prominent superior cerebellar peduncles.The molar tooth aspect is consec- utive to an axonal migration defect (Millen & Gleeson, 2008). The cerebellar vermis often has a “kinked”
appearance, with enlargement of the fourth ventricle.
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Chapter 7 – Malformations
Table 7.2 Clinical features and genetic basis
Loci/genes (mode
Disorders Clinical signs of inheritance)
Molar tooth sign and associated disorders
Classic Joubert syndrome Hypotonia, DD, MR 9q34 (AR)
Oculomotor apraxia Apnea/tachypnea
Joubert syndrome–Leber congenital amaurosis-like Retinal dystrophy with severe visual impairment ? (AR)
Coach syndrome Ocular coloboma ? (AR)
(cerebellar vermis hypoplasia, oligophrenia, ataxia,
coloboma, hepatic fibrosis) Hepatic fibrosis, liver failure
Senior-Løken syndrome Retinal dystrophy, nephronophthisis 2q13; 3q22;
(retinopathy with nephronophthisis) 1p36 (AR)
Dandy-Walker malformation
Classic form Cerebellar vermis hypoplasia 3q24
Dilatation of fourth ventricle Sporadic?
Elevated torcula Multiple
Other forms Other structural malformations associated (chromosomal, syndromic)
Cerebellar vermis hypoplasia
X-linked Cerebellar vermis hypoplasia Xq12
Retrocerebellar cyst, hypotonia, (X-linked) spasticity, seizures
Other (AR?)
Posterior fossa collections Non-communicating membrane– (?)
enclosed cyst; ataxia; hydrocephalus
Pontocerebellar hypoplasia (AR)
Type 1 Spinal muscular atrophy
Respiratory insufficiency ?
Contractures (AR)
Type 2 Microcephaly
Dyskinesia
Poor feeding 7q11–21 (AR)
Seizures
Type 3 Microcephaly
Seizures, spasticity
Congenital disorders of glycosylation Pontocerebellar hypoplasia Ia: 16p13
Hypotonia Ib: 15q22
Stroke-like deficits Ic: 1p22.3
Seizures Id: 3q27
Dysmorphic facies (AR)
Failure to thrive Strabismus Lipodystrophy Inverted nipples
Vomiting, diarrhea, liver dysfunction Kyphoscloliosis
Abbreviations. AR: autosomal recessive; DD: developmental delay; MR: mental retardation.
Adapted from: Parisi and Dobyns (2003).
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CEREBELLAR AGENESIS
A B
Figure 7.1 Cerebellar agenesis. Top panels: Magnetic resonance axial (A) and coronal (B) T2-weighted imaging in a patient with ataxia and nystagmus. A near-complete cerebellar agenesis is observed. The cerebellar remnant comprises anterior quadrangular lobes (arrows). From: Alkan et al.,2009. With permission.
Figure 7.2 Joubert syndrome. Axial T2-weighted image showing an absence of cerebellar vermis and dysplasia of the brainstem.
From: Madsen et al.,2002. With permission.
Dysplasia of cerebellar nuclei and brainstem is very common (Figure 7.2). Breathing deficits may improve with age and even completely disappear. Seizures and autistic behavior have been described. Other abnor- malities include a pigmentary retinopathy, pendu- lar nystagmus, colobomas, cystic dysplasia of the kidneys, and nephronophthisis. Retinal dystrophy and
nephronophthisis are related to defective functions of primary cilia, appendages composed of a mem- brane with a microtubule structure and a centrosome at the base. Several diseases sharing clinical features and the molar tooth sign with Joubert syndrome are categorized in the group of Joubert syndrome and related disorders, such as the orofacial-digital syn- drome type VI, with vermal hypoplasia, tongue hamar- tomas, midline cleftlip, and polydactyly. Recommen- dations for the work-up in all children suspected to present with Joubert syndrome or a related disease are the following: genetics referral to evaluate for consan- guinity, physical examination, peripheral blood kary- otype to exclude a chromosomal disorder, polysomno- gram to identify possible apnea, swallowing studies, EEG monitoring, developmental testing, ophthalmo- logical evaluation including electroretinogram if nec- essary, yearly kidney ultrasound examination, renal and liver function tests, and brain MRI. Children with Joubert syndrome are very sensitive to the respira- tory depressant effects of drugs. Complications of end- stage renal disease resulting from cystic kidney disease or nephronophthisis often require specific treatments, including dialysis and/or kidney transplantation. Indi- viduals with liver failure and/orfibrosis may be candi- dates for portal shunting or orthotopic liver transplan- tation. Polydactyly may require surgery.
Rhombencephalosynapsis is characterized by an absence of the vermis or a severe dysgenesis of mid- line cerebellar structures. There is a fusion of the cerebellar hemispheres, peduncles, and dentate nuclei (Truwit et al., 1991). Fusion of dentate nuclei and inferior colliculi may be associated with a peculiar diamond-shaped fourth ventricle (Utsunomiya et al., 1998). Coronal MRI typically shows horizontally ori- ented folia andfissures.The thalami may also be fused.
Otherfindings include hydrocephalus and absence of a corpus callosum (Toelle et al.,2002). Partial rhomben- cephalosynapsis is characterized by a relatively normal anterior vermis and nodulus, with a deficient posterior vermis and a partial fusion of cerebellar hemispheres (Figure 7.3). This latter malformation can occur in combination with Chiari type II malformation (Wan et al., 2005). Clinical deficits depend on the extent of the cerebellar involvement and the coexistence of supra-tentorial lesions, ranging from mild ataxia to a syndrome of cerebral palsy (Toelle et al., 2002).
Rhombencephalosynapsis is considered to be due to a defect of vermian differentiation occurring between 28 and 40 days of gestation, as a result of impaired
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Chapter 7 – Malformations
PARTIAL RHOMBENCEPHALOSYNAPSIS
A B
Figure 7.3 Rhombencephalosynapsis. Magnetic resonance axial T2-weighted imaging in a patient with partial
rhombencephalosynapsis. Inferior vermian agenesis, fusion of the inferoposterior parts of the cerebellar hemispheres (arrow in left panel), and dysplasia of the superior vermis (short arrows in right panels). From: Alkan et al.,2009. With permission.
expression of a dorsalizing organizer gene (Sarnat et al.,2000).