Terminology in morphological anomalies of the cerebellum does matter
© Poretti and Boltshauser. 2015
Received: 5 June 2015
Accepted: 27 June 2015
Published: 7 July 2015
Neuroimaging plays a key role in the diagnostic work-up of morphological abnormalities of the cerebellum. Diagnostic criteria for numerous morphological anomalies of the cerebellum are based on neuroimaging findings. Various morphological patterns have been described on neuroimaging including cerebellar hypoplasia, cerebellar agenesis, pontocerebellar hypoplasia, cerebellar dysplasia, cerebellar dysmorphia, and cerebellar atrophy. These patterns have specific differential diagnoses. The familiarity with the diagnostic criteria is mandatory for a correct diagnosis and a targeted work-up to avoid unnecessary investigations. A correct diagnosis is essential for early therapy, prognosis, and counseling of the affected children and their family.
KeywordsCerebellum Neuroimaging Cerebellar atrophy Cerebellar hypoplasia Cerebellar dysplasia Cerebellar dysmorphia
Progress in neuroimaging techniques and genetic analysis has led to a significant improvement in definition of morphological abnormalities of the cerebellum. New classifications and checklists of morphological abnormalities of the cerebellum have been proposed [1–3].
Neuroimaging plays a key role in the diagnostic work-up of morphological abnormalities of the cerebellum [4, 5]. Diagnostic criteria for numerous morphological anomalies of the cerebellum are based on neuroimaging findings. Various morphological patterns have been described on neuroimaging including cerebellar hypoplasia, cerebellar agenesis, pontocerebellar hypoplasia, cerebellar dysplasia, cerebellar dysmorphia, and cerebellar atrophy. These patterns have specific differential diagnoses. The familiarity with the diagnostic criteria is mandatory for a correct diagnosis and a targeted work-up to avoid unnecessary investigations. An accurate diagnosis of these complex abnormalities is important for: 1) early institution of the correct therapy, 2) prediction of the prognosis, and 3) counseling of the family including inheritance pattern and risk of recurrence.
Sometimes in the daily clinical work as well as in the scientific literature, the terms mentioned above are used interchangeably. This leads to confusion and may result in misdiagnosis. Semantics does matter in medical and scientific communications . Precision in the use of language, whether verbal or written, is a reflection of precision in scientific thought and patient care.
Here, we will 1) differentiate between cerebellar malformations and cerebellar disruptions and 2) define and discuss various morphological cerebellar patterns including cerebellar agenesis, cerebellar hypoplasia, pontocerebellar hypoplasia, cerebellar dysplasia, cerebellar dysmorphia, and cerebellar atrophy.
Cerebellar malformations versus cerebellar disruptions
The diagnosis of congenital cerebellar anomalies should include the differentiation between inherited (developmental) and acquired (disruptive) abnormalities. A malformation is defined as a congenital morphologic anomaly of a single organ or body part due to cellular and molecular pathways involved in organogenesis; the molecules in these pathways can be altered by gene mutations, teratogens, or combined effects . A disruption is defined as a congenital morphologic anomaly due to the breakdown of a body structure that had a normal developmental potential . Disruptions may be caused by e.g. prenatal infection, hemorrhage, or ischemia and commonly involve the cerebellum . Disruptions are acquired lesions with very low recurrence risk. However, a genetic predisposition to disruptive lesions may be present. Dominant mutations in COL4A1 lead to change of the basal membrane of capillaries resulting in microangiopathy . Within the brain, the microangiopathy may lead to hemorrhage and/or ischemia and result in a spectrum of lesions including porencephaly or unilateral cerebellar hypoplasia [9, 10].
Cerebellar hypoplasia may also present with enlarged cerebellar sulci (mimicking cerebellar atrophy), that is stable over time (in contrast to cerebellar atrophy). Because of the non-progressive course, we prefer the term hypoplasia to describe this imaging pattern [12–14].
Unilateral morphological anomalies of the cerebellum (e.g. unilateral cerebellar hypoplasia and unilateral cerebellar clefts) result from prenatal acquired injuries [15, 16]. In support of this concept, second trimester or early third trimester prenatal cerebellar hemorrhages have been shown by fetal MRI . In addition, some patients have associated destructive lesions such as schizencephaly.
Cerebellar agenesis is defined by the near complete absence of cerebellar tissue with only remnants of the anterior vermis, flocculus, and/or middle cerebellar peduncles (Fig. 1d-e). A secondary pontine hypoplasia is typically seen. The definition of cerebellar agenesis is based on the morphologic pattern and does not suggest the pathogenesis . Cerebellar agenesis may represent a malformation (e.g., mutations in PTF1A)  or a disruption (e.g., hemorrhage that occurs during gestation or in the perinatal period, vascular insufficiency in Chiari II malformation and cerebellar herniation, and as a sequela of prematurity) [2, 19].
The term pontocerebellar hypoplasia is often used in a descriptive manner to imply that the volume of the cerebellum and the pons is reduced. On the other hand, it is used specifically to refer to the pontocerebellar hypoplasias conceptualized by Peter Barth as early (prenatal) onset degenerative disorder (types 1, 2, 4, 5, 6, and 7) . In this sense, the term “hypoplasia” is misleading and atrophy would be more accurate. In the last years, however, diseases with a non-progressive course have been included in the heterogeneous group of pontocerebellar hypoplasias (types 3 and 8). Listing in OMIM does not reflect pathogenesis.
Pontocerebellar hypoplasias as conceptualized by Peter Barth have a peculiar neuroimaging pattern including more pronounced involvement of the cerebellar hemispheres compared to the vermis and reduction in size of the pons (Fig. 1f-g) . Predominant involvement of the cerebellar hemispheres is unusual and results in a “dragonfly” appearance on coronal images: flattened cerebellar hemispheres represent “the wings”, while the relatively preserved vermis represents “the body”. A “dragonfly” appearance has been shown also in very low birth weight (less than 1500 g) premature infants born before 32 weeks of gestation  and CASK mutations .
Reduction in size of the pons is not seen in the vast majority of diseases associated with cerebellar atrophy with postnatal onset . Pontine hypoplasia however is a feature of diseases associated with prenatal loss of cerebellar tissue: 1) hereditary disorders with prenatal onset cerebellar atrophy including the group of pontocerebellar hypoplasias  and congenital disorder of glycosylation type 1a due to PMM2 mutations , and 2) acquired disorders with prenatal onset cerebellar disruptive lesions such as cerebellar agenesis  and vanishing cerebellum in myelomeningocele , and anencephaly . In addition, marked reduction in size of the pons has been shown in very low birth weight (less than 1500 g) premature infants born before 32 weeks of gestation [22, 27].
Cerebellar dysplasia is defined by abnormal cerebellar foliation, white matter arborization, and gray-white matter junction (Fig. 1h). Dysplasia may globally involve the cerebellum or affect only one cerebellar hemisphere. In addition, cerebellar dysplasia may be associated with cortical/subcortical cysts . Cerebellar cysts are likely the result of disturbed cortical migration/organization and pial membrane disruption and are most likely formed from the subarachnoid spaces that were engulfed by the dysplastic cerebellar folia, particularly in the boundary between the normal and dysplastic cerebellar cortex.
Global cerebellar dysplasia has been reported in a few posterior fossa malformations including Chudley-McCullough syndrome , α-dystroglycanopathies , GPR56-related polymicrogyria , and Poretti-Boltshauser syndrome due to LAMA1 mutations [32, 33]. In α-dystroglycanopathies , GPR56-related polymicrogyria , and Poretti-Boltshauser syndrome due to LAMA1 mutations [32, 33], cerebellar dysplasia is typically associated with cerebellar cysts. Diagonal folia across the vermis on axial images have been reported in tubulinopathies . Dysplasia of the superior cerebellar vermis is generally seen in Joubert syndrome and can be very helpful when the other neuroimaging features (e.g. the molar tooth sign) are subtle or distorted . Finally, cerebellar dysplasia may be the result of a disruptive process such as a prenatal hemorrhage. Disruptive cerebellar dysplasia may be uni- or bilateral and the affected hemispheres may be reduced in volume. In prenatal cerebellar disruptions, focal cerebellar dysplasia is typically confined to the region of the disrupted injury such as a cerebellar cleft . In a few patients, disruptive cerebellar dysplasia may be associated with focal cerebellar cysts . For specific diagnosis, it is important to determine the pattern of dysplasia and the presence of cerebellar cysts (Fig. 1i) and correlate them with clinical information .
Lhermitte-Duclos disease or “dysplastic cerebellar gangliocytoma” (OMIM 158350) is a rare disorder of the cerebellum that is usually included into the group of focal cerebellar dysplasia . In contrast to Chudley-McCullough syndrome, α-dystroglycanopathies, GPR56-related polymicrogyria, and Poretti-Boltshauser syndrome, in Lhermitte-Duclos disease the orientation of the cerebellar foliae is preserved, while the volume of multiple cerebellar foliae is diffusely increased . This results in a characteristic neuroimaging pattern of localized lamellar hypertrophy: the inner portions of the folia are T1 hypointense and T2 hyperintense, while the outer portions are T1 isointense and T2 iso- to hypointense.
Cerebellar dysmorphia is a term that we recently coined to refer to peculiar morphological anomalies that we saw in few patients with neurofibromatosis type 1 . Cerebellar dysmorphia refers to enlargement of a cerebellar hemisphere with widening of the interfolial spaces of its posterior part, which is bulky (like an appendicular portion of additional cerebellar tissue) and crosses the midline (Fig. 1j-k).
Cerebellar atrophy is a relatively common neuroimaging finding in pediatric neurology and neuroradiology. Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue (Fig. 1l) . Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Cerebellar atrophy is a non-specific neuroimaging finding and has been associated with a long list of pediatric diseases including genetic and acquired causes. We proposed a pattern recognition approach for hereditary pediatric cerebellar atrophy . We differentiated between isolated (“pure”) cerebellar atrophy and cerebellar atrophy associated (“plus”) with additional neuroimaging findings including hypomyelination, progressive white matter abnormalities, signal change of the dentate nucleus, cerebellar cortex T2-hyperintensity, and basal ganglia involvement.
The distinction between cerebellar atrophy and cerebellar hypoplasia is not difficult in theory, but can be problematic or impossible in practice based on a single examination. In children with non-progressive cerebellar ataxia (i.e. with an obviously longstanding static situation), enlarged cerebellar sulci mimicking cerebellar atrophy CA may be seen and are stable over time (stable follow-up up to 20 years) [12–14]. In this situation, we prefer the term cerebellar hypoplasia because of the non-progressive course of clinical and neuroimaging findings and favor a malformative instead of a degenerative pathomechanism. In addition, cerebellar atrophy may be superimposed to cerebellar hypoplasia as shown in some forms of pontocerebellar hypoplasia and some children with congenital disorder of glycosylation type 1a [21, 24].
- Poretti A, Wolf NI, Boltshauser E. Differential diagnosis of cerebellar atrophy in childhood. Eur J Paediatr Neurol. 2008;12(3):155–67.PubMedView ArticleGoogle Scholar
- Poretti A, Prayer D, Boltshauser E. Morphological spectrum of prenatal cerebellar disruptions. Eur J Paediatr Neurol. 2009;13(5):397–407.PubMedView ArticleGoogle Scholar
- Barkovich AJ, Millen KJ, Dobyns WB. A developmental and genetic classification for midbrain-hindbrain malformations. Brain. 2009;132(Pt 12):3199–230.PubMed CentralPubMedView ArticleGoogle Scholar
- Bosemani T, Orman G, Boltshauser E, Tekes A, Huisman TA, Poretti A. Congenital abnormalities of the posterior fossa. Radiographics. 2015;35(1):200–20.PubMedView ArticleGoogle Scholar
- Arora R. Imaging spectrum of cerebellar pathologies: a pictorial essay. Pol J Radiol. 2015;80:142–50.PubMed CentralPubMedView ArticleGoogle Scholar
- Sarnat HB. Semantics do matter! Precision in scientific communication in pediatric neurology. J Child Neurol. 2007;22(11):1245–51.PubMedView ArticleGoogle Scholar
- Hennekam RC, Biesecker LG, Allanson JE, Hall JG, Opitz JM, Temple IK, et al. Elements of morphology: general terms for congenital anomalies. Am J Med Genet A. 2013;161A(11):2726–33.PubMedView ArticleGoogle Scholar
- Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS, Schimenti JC, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science. 2005;308(5725):1167–71.PubMedView ArticleGoogle Scholar
- Vermeulen RJ, Peeters-Scholte C, Van Vugt JJ, Barkhof F, Rizzu P, van der Schoor SR, et al. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. Neuropediatrics. 2011;42(1):1–3.PubMedView ArticleGoogle Scholar
- Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Ann Neurol. 2013;73(1):48–57.PubMedView ArticleGoogle Scholar
- Poretti A, Boltshauser E, Doherty D. Cerebellar hypoplasia: Differential diagnosis and diagnostic approach. Am J Med Genet C: Semin Med Genet. 2014;166(2):211–26.View ArticleGoogle Scholar
- Yapici Z, Eraksoy M. Non-progressive congenital ataxia with cerebellar hypoplasia in three families. Acta Paediatr. 2005;94(2):248–53.PubMedView ArticleGoogle Scholar
- Turkmen S, Demirhan O, Hoffmann K, Diers A, Zimmer C, Sperling K, et al. Cerebellar hypoplasia and quadrupedal locomotion in humans as a recessive trait mapping to chromosome 17p. J Med Genet. 2006;43(5):461–4.PubMed CentralPubMedView ArticleGoogle Scholar
- Boltshauser E, Poretti A. Nonprogressive congenital ataxia. In: Boltshauser E, Schmahmann JD, editors. Cerebelalr disorders in children. London: Mac Keith Press; 2012. p. 135–9.Google Scholar
- Poretti A, Leventer RJ, Cowan FM, Rutherford MA, Steinlin M, Klein A, et al. Cerebellar cleft: a form of prenatal cerebellar disruption. Neuropediatrics. 2008;39(2):106–12.PubMedView ArticleGoogle Scholar
- Poretti A, Limperopoulos C, Roulet-Perez E, Wolf NI, Rauscher C, Prayer D, et al. Outcome of severe unilateral cerebellar hypoplasia. Dev Med Child Neurol. 2010;52(8):718–24.PubMedView ArticleGoogle Scholar
- Malinger G, Zahalka N, Kidron D, Ben-Sira L, Lev D, Lerman-Sagie T. Fatal outcome following foetal cerebellar haemorrhage associated with placental thrombosis. Eur J Paediatr Neurol. 2006;10(2):93–6.PubMedView ArticleGoogle Scholar
- Sellick GS, Barker KT, Stolte-Dijkstra I, Fleischmann C, Coleman RJ, Garrett C, et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet. 2004;36(12):1301–5.PubMedView ArticleGoogle Scholar
- Poretti A, Risen S, Meoded A, Northington FJ, Johnston MV, Boltshauser E, et al. Cerebellar agenesis: an extreme form of cerebellar disruption in preterm neonates. J Pediatr Neuroradiol. 2013;2:163–7.Google Scholar
- Namavar Y, Barth PG, Poll-The BT, Baas F. Classification, diagnosis and potential mechanisms in pontocerebellar hypoplasia. Orphanet J Rare Dis. 2011;6:50.PubMed CentralPubMedView ArticleGoogle Scholar
- Namavar Y, Barth PG, Kasher PR, van Ruissen F, Brockmann K, Bernert G, et al. Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. Brain. 2011;134(Pt 1):143–56.PubMedView ArticleGoogle Scholar
- Messerschmidt A, Brugger PC, Boltshauser E, Zoder G, Sterniste W, Birnbacher R, et al. Disruption of cerebellar development: potential complication of extreme prematurity. AJNR Am J Neuroradiol. 2005;26(7):1659–67.PubMedGoogle Scholar
- Burglen L, Chantot-Bastaraud S, Garel C, Milh M, Touraine R, Zanni G, et al. Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient. Orphanet J Rare Dis. 2012;7:18.PubMed CentralPubMedView ArticleGoogle Scholar
- Feraco P, Mirabelli-Badenier M, Severino M, Alpigiani MG, Di Rocco M, Biancheri R, et al. The shrunken, bright cerebellum: a characteristic MRI finding in congenital disorders of glycosylation type 1a. AJNR Am J Neuroradiol. 2012;33(11):2062–7.PubMedView ArticleGoogle Scholar
- Boltshauser E, Schneider J, Kollias S, Waibel P, Weissert M. Vanishing cerebellum in myelomeningocoele. Eur J Paediatr Neurol. 2002;6(2):109–13.PubMedView ArticleGoogle Scholar
- Poretti A, Meoded A, Ceritoglu E, Boltshauser E, Huisman TA. Postnatal in-vivo MRI findings in anencephaly. Neuropediatrics. 2010;41(6):264–6.PubMedView ArticleGoogle Scholar
- Zafeiriou DI, Ververi A, Anastasiou A, Soubasi V, Vargiami E. Pontocerebellar hypoplasia in extreme prematurity: clinical and neuroimaging findings. Pediatr Neurol. 2013;48(1):48–51.PubMedView ArticleGoogle Scholar
- Boltshauser E, Scheer I, Huisman TA, Poretti A. Cerebellar cysts in children: a pattern recognition approach. Cerebellum. 2015;14(3):308–16.PubMedView ArticleGoogle Scholar
- Doherty D, Chudley AE, Coghlan G, Ishak GE, Innes AM, Lemire EG, et al. GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome. Am J Hum Genet. 2012;90(6):1088–93.PubMed CentralPubMedView ArticleGoogle Scholar
- Clement E, Mercuri E, Godfrey C, Smith J, Robb S, Kinali M, et al. Brain involvement in muscular dystrophies with defective dystroglycan glycosylation. Ann Neurol. 2008;64(5):573–82.PubMedView ArticleGoogle Scholar
- Bahi-Buisson N, Poirier K, Boddaert N, Fallet-Bianco C, Specchio N, Bertini E, et al. GPR56-related bilateral frontoparietal polymicrogyria: further evidence for an overlap with the cobblestone complex. Brain. 2010;133(11):3194–209.PubMedView ArticleGoogle Scholar
- Poretti A, Hausler M, von Moers A, Baumgartner B, Zerres K, Klein A, et al. Ataxia, intellectual disability, and ocular apraxia with cerebellar cysts: a new disease? Cerebellum. 2014;13(1):79–88.PubMedView ArticleGoogle Scholar
- Aldinger KA, Mosca SJ, Tetreault M, Dempsey JC, Ishak GE, Hartley T, et al. Mutations in LAMA1 cause cerebellar dysplasia and cysts with and without retinal dystrophy. Am J Hum Genet. 2014;95(2):227–34.PubMed CentralPubMedView ArticleGoogle Scholar
- Bahi-Buisson N, Poirier K, Fourniol F, Saillour Y, Valence S, Lebrun N, et al. The wide spectrum of tubulinopathies: what are the key features for the diagnosis? Brain. 2014;137(Pt 6):1676–700.PubMedView ArticleGoogle Scholar
- Poretti A, Huisman TA, Scheer I, Boltshauser E. Joubert syndrome and related disorders: spectrum of neuroimaging findings in 75 patients. AJNR Am J Neuroradiol. 2011;32(8):1459–63.PubMedView ArticleGoogle Scholar
- Nowak DA, Trost HA. Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma): a malformation, hamartoma or neoplasm? Acta Neurol Scand. 2002;105(3):137–45.PubMedView ArticleGoogle Scholar
- Poretti A, Meoded A, Huisman TA. Neuroimaging of pediatric posterior fossa tumors including review of the literature. J Magn Reson Imaging. 2012;35(1):32–47.PubMedView ArticleGoogle Scholar
- Toelle SP, Poretti A, Weber P, Seute T, Bromberg JE, Scheer I et al. Cerebellar Hypoplasia and Dysmorphia in Neurofibromatosis Type 1. Cerebellum. 2015;epub Mar 3.Google Scholar
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.