Posterior Fossa in Primary Microcephaly: Relationships between Forebrain and Mid-Hindbrain Size in 110 Patients

Abstract

Microcephalies vary widely in clinical severity and in morphology. The purpose of this study is to determine the frequency of disproportion between the size of the cerebrum and the size of midbrain and hindbrain structures in infants and children with microcephaly, as analysis of such disproportions might aid understanding of these disorders and facilitate testing for specific genetic causes. The relative sizes of the forebrain, each component of the brain stem, and vermis and hemispheres of the cerebellum were analyzed visually on magnetic resonance (MR) images of 110 microcephalic patients. A disproportionally large cerebellum, compared with the cerebrum, was found in 50 cases (45.5%), a proportional cerebellum in 49 cases (44.5%), and a disproportionally small cerebellum in 11 cases (10%). Proportional cerebella were most common in mild (86%) and moderate (55%) microcephaly patients, whereas disproportionately large cerebella were most common in severe (57%) and moderate (32%) microcephaly. Disproportionately small cerebella were seen only in moderate (13%) and severe (9%) microcephaly. As genes are expressed at different times in cerebral and cerebellar development, it is postulated that analysis of relative cerebellar and brain stem size may be useful in the initial analysis of microcephaly by MR images both to categorize and to help determine likely genetic causes.

Keywords

primary microcephaly - cerebellar hypoplasia - pontocerebellar hypoplasia

• References

• 1 Warkany J, Lemire RJ, Cohen Jr MM. Mental Retardation and Congenital Malformations of the Central Nervous System. Chicago, IL: Yearbook; 1981: 28-30
• 2 Berg BO. Developmental disorders of the nervous system. In: Berg BO, , ed. Principles of Child Neurology. New York, NY: McGraw-Hill; 1996: 665-90
• 3 Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB. A developmental and genetic classification for malformations of cortical development: update 2012. Brain 2012; 135 (Pt 5) 1348-1369
• 4 Mochida GH, Walsh CA. Molecular genetics of human microcephaly. Curr Opin Neurol 2001; 14 (2) 151-156
• 5 Mahmood S, Ahmad W, Hassan MJ. Autosomal Recessive Primary Microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum. Orphanet J Rare Dis 2011; 6: 39
• 6 Hansen DV, Lui JH, Parker PR, Kriegstein AR. Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 2010; 464 (7288) 554-561
• 7 Adachi Y, Poduri A, Kawaguch A , et al. Congenital microcephaly with a simplified gyral pattern: associated findings and their significance. AJNR Am J Neuroradiol 2011; 32 (6) 1123-1129
• 8 Bilgüvar K, Oztürk AK, Louvi A , et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 2010; 467 (7312) 207-210
• 9 Barth PG, Blennow G, Lenard HG , et al. The syndrome of autosomal recessive pontocerebellar hypoplasia, microcephaly, and extrapyramidal dyskinesia (pontocerebellar hypoplasia type 2): compiled data from 10 pedigrees. Neurology 1995; 45 (2) 311-317
• 10 Hashimoto K, Takeuchi Y, Kida Y , et al. Three siblings of fatal infantile encephalopathy with olivopontocerebellar hypoplasia and microcephaly. Brain Dev 1998; 20 (3) 169-174
• 11 Albrecht S, Schneider MC, Belmont J, Armstrong DL. Fatal infantile encephalopathy with olivopontocerebellar hypoplasia and micrencephaly. Report of three siblings. Acta Neuropathol 1993; 85 (4) 394-399
• 12 Peiffer J, Pfeiffer RA. Hypoplasia ponto-neocerebellaris (author's transl). J Neurol 1977; 215 (4) 241-251
• 13 Vuia O. Congenital spongy degeneration of the brain (van Bogaert Bertrand) associated with micrencephaly and ponto-cerebellar atrophy (contributions to the pathology of glial dystrophy of intrauterin origin). Neuropadiatrie 1977; 8 (1) 73-87
• 14 Sztriha L, Johansen JG, Al-Gazali LI. Extreme microcephaly with agyria-pachygyria, partial agenesis of the corpus callosum, and pontocerebellar dysplasia. J Child Neurol 2005; 20 (2) 170-172
• 15 Rajab A, Mochida GH, Hill A , et al. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology 2003; 60 (10) 1664-1667
• 16 Barkovich AJ, Ferriero DM, Barr RM , et al. Microlissencephaly: a heterogeneous malformation of cortical development. Neuropediatrics 1998; 29 (3) 113-119
• 17 Bellini C, Mazzella M, Arioni C, Fondelli MP, Serra G. “Apple-peel” intestinal atresia, ocular anomalies, and microcephaly syndrome: brain magnetic resonance imaging study. Am J Med Genet 2002; 110 (2) 176-178
• 18 Kelley RI, Robinson D, Puffenberger EG, Strauss KA, Morton DH. Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria. Am J Med Genet 2002; 112 (4) 318-326
• 19 Sheen VL, Ganesh VS, Topcu M , et al. Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat Genet 2004; 36 (1) 69-76
• 20 Chandler KE, Del Rio A, Rakshi K , et al. Leucodysplasia, microcephaly, cerebral malformation (LMC): a novel recessive disorder linked to 2p16. Brain 2006; 129 (Pt 1) 272-277
• 21 Barkovich AJ. Normal development of the neonatal and infant brain, skull, and spine. In: Barkovich AJ, , ed. Pediatric Neuroimaging, 5th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2012: 20-52
• 22 Barkovich AJ. MR imaging of the neonatal brain. Neuroimaging Clin N Am 2006; 16 (1) 117-135 , viii–ix
• 23 Barkovich AJ, Kjos BO. Normal postnatal development of the corpus callosum as demonstrated by MR imaging. AJNR Am J Neuroradiol 1988; 9 (3) 487-491
• 24 Doherty D, Millen KJ, Barkovich AJ. Midbrain and hindbrain malformations: advances in clinical diagnosis, imaging, and genetics. Lancet Neurol 2013; 12 (4) 381-393
• 25 Hevner RF, Hodge RD, Daza RA, Englund C. Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus. Neurosci Res 2006; 55 (3) 223-233
• 26 Donkelaar HJ, Lammens M, Wesseling P , et al. Development and developmental disorders of the human cerebellum. In: Donkelaar HJ, Lammens M, Hori A, . eds. Clinical Neuroembryology: Development and Developmental Disorders of the Human Central Nervous System. Springer, Berlin–Heidelberg; 2006: 309-314
• 27 Mochida GH, Ganesh VS, de Michelena MI , et al. CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development. Nat Genet 2012; 44 (11) 1260-1264
• 28 Poduri A, Evrony GD, Cai X , et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 2012; 74 (1) 41-48
• 29 Boland E, Clayton-Smith J, Woo VG , et al. Mapping of deletion and translocation breakpoints in 1q44 implicates the serine/threonine kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum. Am J Hum Genet 2007; 81 (2) 292-303
• 30 Lee JH, Huynh M, Silhavy JL , et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet 2012; 44 (8) 941-945
• 31 Bakircioglu M, Carvalho OP, Khurshid M , et al. The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis. Am J Hum Genet 2011; 88 (5) 523-535
• 32 Alkuraya FS, Cai X, Emery C , et al. Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]. Am J Hum Genet 2011; 88 (5) 536-547
• 33 Baala L, Briault S, Etchevers HC , et al. Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis. Nat Genet 2007; 39 (4) 454-456
• 34 O'Driscoll MC, Daly SB, Urquhart JE , et al. Recessive mutations in the gene encoding the tight junction protein occludin cause band-like calcification with simplified gyration and polymicrogyria. Am J Hum Genet 2010; 87 (3) 354-364
• 35 Borck G, Wunram H, Steiert A , et al. A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome. Hum Genet 2011; 129 (1) 45-50
• 36 Juric-Sekhar G, Kapur RP, Glass IA, Murray ML, Parnell SE, Hevner RF. Neuronal migration disorders in microcephalic osteodysplastic primordial dwarfism type I/III. Acta Neuropathol 2011; 121 (4) 545-554
• 37 Bicknell LS, Walker S, Klingseisen A , et al. Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nat Genet 2011; 43 (4) 350-355
• 38 Barkovich AJ, Millen KJ, Dobyns WB. A developmental classification of malformations of the brainstem. Ann Neurol 2007; 62 (6) 625-639
• 39 Barth PG, Majoie CB, Caan MW , et al. Pontine tegmental cap dysplasia: a novel brain malformation with a defect in axonal guidance. Brain 2007; 130 (Pt 9) 2258-2266
• 40 Jissendi-Tchofo P, Doherty D, McGillivray G , et al. Pontine tegmental cap dysplasia: MR imaging and diffusion tensor imaging features of impaired axonal navigation. AJNR Am J Neuroradiol 2009; 30 (1) 113-119
• 41 Najm J, Horn D, Wimplinger I , et al. Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat Genet 2008; 40 (9) 1065-1067
• 42 Kortüm F, Das S, Flindt M , et al. The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. J Med Genet 2011; 48 (6) 396-406