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Pontocerebellar Hypoplasia: a Pattern Recognition Approach

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Abstract

Pontocerebellar hypoplasias (PCH) represent a heterogeneous group of very rare disorders with reduced volume of pons and cerebellum. The term is purely descriptive and does not imply a genetic progressive disease. Currently (as of Jan 01, 2020), 13 different types are listed in OMIM (Online Mendelian Inheritance in Man), associated with 19 different genes. However, a large group of similar imaging patterns is known, and it is unclear why some are labeled as PCH, while others are not. The latter include CASK- and VLDLR-associated disorders, some tubulinopathies, certain dystroglycanopathies, a few congenital disorders of glycosylation (CDG) syndromes, several forms associated with rare variants (e.g., DCK1, WDR81, ITPR1), and “cerebellar disruption of prematurity”—an acquired etiology. The objective of this paper is to elaborate a pattern recognition approach, mainly imaging-based, to facilitate a timely and accurate diagnosis, to narrow the differential diagnosis, and to enable targeted additional (genetic) investigations. We describe magnetic resonance imaging (MRI) findings and offer “checklists” for infratentorial findings (e.g., non-lobulated vermis, dragonfly pattern of the cerebellum, cerebellar cysts, brainstem kinking, longitudinal grooves along the brainstem, flat pons) as well as for supratentorial anomalies (e.g., agenesis of corpus callosum, optic atrophy, simplified gyral pattern, and hypomyelination). The clinical context and laboratory investigations need to be considered as well. We also provide a “checklist” for clinical features. A systematic analysis of imaging and clinical features can assist in narrowing the differential diagnosis and permitting more targeted genetic testing. Some imaging patterns are diagnostic.

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References

  1. Barth PG, Vrensen GF, Uylings HB, Oorthuys JW, Stam FC. Inherited syndrome of microcephaly, dyskinesia and pontocerebellar hypoplasia: a systemic atrophy with early onset. J Neurol Sci. 1990;97:25–42.

    CAS  PubMed  Google Scholar 

  2. Barth PG. Pontocerebellar hypoplasias. An overview of a group of inherited neurodegenerative disorders with fetal onset. Brain Dev. 1993;15:411–22.

    CAS  PubMed  Google Scholar 

  3. Renbaum P, Kellerman E, Jaron R, Geiger D, Segel R, Lee M, et al. Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene. Am J Hum Genet. 2009;85:281–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Biancheri R, Cassandrini D, Pinto F, Trovato R, Di Rocco M, Mirabelli-Badenier M, et al. EXOSC3 mutations in isolated cerebellar hypoplasia and spinal anterior horn involvement. J Neurol. 2013;260:1866–70.

    CAS  PubMed  Google Scholar 

  5. Boczonadi V, Muller JS, Pyle A, Munkley J, Dor T, Quartararo J, et al. EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia. Nat Commun. 2014;5:4287.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Burns DT, Donkervoort S, Muller JS, Knierim E, Bharucha-Goebel D, Faqeih EA, et al. Variants in EXOSC9 disrupt the RNA exosome and result in cerebellar atrophy with spinal motor neuronopathy. Am J Hum Genet. 2018;102:858–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Budde BS, Namavar Y, Barth PG, Poll-The BT, Nurnberg G, Becker C, et al. tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat Genet. 2008;40:1113–8.

    CAS  PubMed  Google Scholar 

  8. Bierhals T, Korenke GC, Uyanik G, Kutsche K. Pontocerebellar hypoplasia type 2 and TSEN2: review of the literature and two novel mutations. Eur J Med Genet. 2013;56:325–30.

    PubMed  Google Scholar 

  9. Agamy O, Ben Zeev B, Lev D, Marcus B, Fine D, Su D, et al. Mutations disrupting selenocysteine formation cause progressive cerebello-cerebral atrophy. Am J Hum Genet. 2010;87:538–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Feinstein M, Flusser H, Lerman-Sagie T, Ben-Zeev B, Lev D, Agamy O, et al. VPS53 mutations cause progressive cerebello-cerebral atrophy type 2 (PCCA2). J Med Genet. 2014;51:303–8.

    CAS  PubMed  Google Scholar 

  11. Breuss MW, Sultan T, James KN, Rosti RO, Scott E, Musaev D, et al. Autosomal-recessive mutations in the tRNA splicing endonuclease subunit TSEN15 cause pontocerebellar hypoplasia and progressive microcephaly. Am J Hum Genet. 2016;99:785.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Marin-Valencia I, Gerondopoulos A, Zaki MS, Ben-Omran T, Almureikhi M, Demir E, et al. Homozygous mutations in TBC1D23 lead to a non-degenerative form of pontocerebellar hypoplasia. Am J Hum Genet. 2017;101:441–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 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;134:143–56.

    PubMed  Google Scholar 

  14. 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  PubMed Central  Google Scholar 

  15. Rudnik-Schoneborn S, Barth PG, Zerres K. Pontocerebellar hypoplasia. Am J Med Genet C Semin Med Genet. 2014;166C:173–83.

    PubMed  Google Scholar 

  16. van Dijk T, Baas F, Barth PG, Poll-The BT. What’s new in pontocerebellar hypoplasia? An update on genes and subtypes. Orphanet J Rare Dis. 2018;13:92.

    PubMed  PubMed Central  Google Scholar 

  17. Cassandrini D, Cilio MR, Bianchi M, Doimo M, Balestri M, Tessa A, et al. Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients. J Inherit Metab Dis. 2013;36:43–53.

    CAS  PubMed  Google Scholar 

  18. Schaffer AE, Eggens VR, Caglayan AO, Reuter MS, Scott E, Coufal NG, et al. CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration. Cell. 2014;157:651–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Luhl S, Bode H, Schlotzer W, Bartsakoulia M, Horvath R, Abicht A, et al. Novel homozygous RARS2 mutation in two siblings without pontocerebellar hypoplasia - further expansion of the phenotypic spectrum. Orphanet J Rare Dis. 2016;11:140.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Nishri D, Goldberg-Stern H, Noyman I, Blumkin L, Kivity S, Saitsu H, et al. RARS2 mutations cause early onset epileptic encephalopathy without ponto-cerebellar hypoplasia. Eur J Paediatr Neurol. 2016;20:412–7.

    PubMed  Google Scholar 

  21. Moog U, Bierhals T, Brand K, Bautsch J, Biskup S, Brune T, et al. Phenotypic and molecular insights into CASK-related disorders in males. Orphanet J Rare Dis. 2015;10:44.

    PubMed  PubMed Central  Google Scholar 

  22. Takanashi J, Okamoto N, Yamamoto Y, Hayashi S, Arai H, Takahashi Y, et al. Clinical and radiological features of Japanese patients with a severe phenotype due to CASK mutations. Am J Med Genet A. 2012;158A:3112–8.

    PubMed  Google Scholar 

  23. Chou SM, Gilbert EF, Chun RW, Laxova R, Tuffli GA, Sufit RL, et al. Infantile olivopontocerebellar atrophy with spinal muscular atrophy (infantile OPCA + SMA). Clin Neuropathol. 1990;9:21–32.

    CAS  PubMed  Google Scholar 

  24. Eggens VR, Barth PG, Niermeijer JM, Berg JN, Darin N, Dixit A, et al. EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations. Orphanet J Rare Dis. 2014;9:23.

    PubMed  PubMed Central  Google Scholar 

  25. Rudnik-Schoneborn S, Senderek J, Jen JC, Houge G, Seeman P, Puchmajerova A, et al. Pontocerebellar hypoplasia type 1: clinical spectrum and relevance of EXOSC3 mutations. Neurology. 2013;80:438–46.

    PubMed  PubMed Central  Google Scholar 

  26. Wojcik MH, Okada K, Prabhu SP, Nowakowski DW, Ramsey K, Balak C, et al. De novo variant in KIF26B is associated with pontocerebellar hypoplasia with infantile spinal muscular atrophy. Am J Med Genet A. 2018;176:2623–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wan J, Steffen J, Yourshaw M, Mamsa H, Andersen E, Rudnik-Schoneborn S, et al. Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia. Brain. 2016;139:2877–90.

    PubMed  PubMed Central  Google Scholar 

  28. van Dijk T, Rudnik-Schoneborn S, Senderek J, Hajmousa G, Mei H, Dusl M, et al. Pontocerebellar hypoplasia with spinal muscular atrophy (PCH1): identification of SLC25A46 mutations in the original Dutch PCH1 family. Brain. 2017;140:e46.

    PubMed  Google Scholar 

  29. Barth PG, Blennow G, Lenard HG, Begeer JH, van der Kley JM, Hanefeld F, et al. The syndrome of autosomal recessive pontocerebellar hypoplasia, microcephaly, and extrapyramidal dyskinesia (pontocerebellar hypoplasia type 2): compiled data from 10 pedigrees. Neurology. 1995;45:311–7.

    CAS  PubMed  Google Scholar 

  30. Sanchez-Albisua I, Frolich S, Barth PG, Steinlin M, Krageloh-Mann I. Natural course of pontocerebellar hypoplasia type 2A. Orphanet J Rare Dis. 2014;9:70.

    PubMed  PubMed Central  Google Scholar 

  31. Ben-Zeev B, Hoffman C, Lev D, Watemberg N, Malinger G, Brand N, et al. Progressive cerebellocerebral atrophy: a new syndrome with microcephaly, mental retardation, and spastic quadriplegia. J Med Genet. 2003;40:e96.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Pavlidou E, Salpietro V, Phadke R, Hargreaves IP, Batten L, McElreavy K, et al. Pontocerebellar hypoplasia type 2D and optic nerve atrophy further expand the spectrum associated with selenoprotein biosynthesis deficiency. Eur J Paediatr Neurol. 2016;20:483–8.

    PubMed  Google Scholar 

  33. Liewen H, Meinhold-Heerlein I, Oliveira V, Schwarzenbacher R, Luo G, Wadle A, et al. Characterization of the human GARP (Golgi associated retrograde protein) complex. Exp Cell Res. 2005;306:24–34.

    CAS  PubMed  Google Scholar 

  34. Alazami AM, Patel N, Shamseldin HE, Anazi S, Al-Dosari MS, Alzahrani F, et al. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 2015;10:148–61.

    CAS  PubMed  Google Scholar 

  35. Ahmed MY, Chioza BA, Rajab A, Schmitz-Abe K, Al-Khayat A, Al-Turki S, et al. Loss of PCLO function underlies pontocerebellar hypoplasia type III. Neurology. 2015;84:1745–50.

    PubMed  PubMed Central  Google Scholar 

  36. Rajab A, Mochida GH, Hill A, Ganesh V, Bodell A, Riaz A, et al. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology. 2003;60:1664–7.

    CAS  PubMed  Google Scholar 

  37. Durmaz B, Wollnik B, Cogulu O, Li Y, Tekgul H, Hazan F, et al. Pontocerebellar hypoplasia type III (CLAM): extended phenotype and novel molecular findings. J Neurol. 2009;256:416–9.

    CAS  PubMed  Google Scholar 

  38. Albrecht S, Schneider MC, Belmont J, Armstrong DL. Fatal infantile encephalopathy with olivopontocerebellar hypoplasia and micrencephaly. Report of three siblings. Acta Neuropathol. 1993;85:394–9.

    CAS  PubMed  Google Scholar 

  39. Patel MS, Becker LE, Toi A, Armstrong DL, Chitayat D. Severe, fetal-onset form of olivopontocerebellar hypoplasia in three sibs: PCH type 5? Am J Med Genet A. 2006;140:594–603.

    PubMed  Google Scholar 

  40. Namavar Y, Chitayat D, Barth PG, van Ruissen F, de Wissel MB, Poll-The BT, et al. TSEN54 mutations cause pontocerebellar hypoplasia type 5. Eur J Hum Genet. 2011;19:724–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Anderson C, Davies JH, Lamont L, Foulds N. Early pontocerebellar hypoplasia with vanishing testes: a new syndrome? Am J Med Genet A. 2011;155A:667–72.

    PubMed  Google Scholar 

  42. Mahbubul Huq AH, Nigro MA. XY sex reversal and a nonprogressive neurologic disorder: a new syndrome? Pediatr Neurol. 2000;23:357–60.

    CAS  PubMed  Google Scholar 

  43. Lardelli RM, Schaffer AE, Eggens VR, Zaki MS, Grainger S, Sathe S, et al. Biallelic mutations in the 3′ exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. Nat Genet. 2017;49:457–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Mochida GH, Ganesh VS, de Michelena MI, Dias H, Atabay KD, Kathrein KL, et al. CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development. Nat Genet. 2012;44:1260–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Akizu N, Cantagrel V, Schroth J, Cai N, Vaux K, McCloskey D, et al. AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder. Cell. 2013;154:505–17.

    CAS  PubMed  Google Scholar 

  46. Kortum F, Jamra RA, Alawi M, Berry SA, Borck G, Helbig KL, et al. Clinical and genetic spectrum of AMPD2-related pontocerebellar hypoplasia type 9. Eur J Hum Genet. 2018;26:695–708.

    PubMed  PubMed Central  Google Scholar 

  47. Marsh AP, Lukic V, Pope K, Bromhead C, Tankard R, Ryan MM, et al. Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss. Neurol Genet. 2015;1:e16.

    PubMed  PubMed Central  Google Scholar 

  48. Karaca E, Weitzer S, Pehlivan D, Shiraishi H, Gogakos T, Hanada T, et al. Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function. Cell. 2014;157:636–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Ivanova EL, Mau-Them FT, Riazuddin S, Kahrizi K, Laugel V, Schaefer E, et al. Homozygous truncating variants in TBC1D23 cause pontocerebellar hypoplasia and alter cortical development. Am J Hum Genet. 2017;101:428–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. van Dijk T, Ferdinandusse S, Ruiter JPN, Alders M, Mathijssen IB, Parboosingh JS, et al. Biallelic loss of function variants in COASY cause prenatal onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis. Eur J Hum Genet. 2018;26:1752–8.

    PubMed  PubMed Central  Google Scholar 

  51. Gershlick DC, Ishida M, Jones JR, Bellomo A, Bonifacino JS, Everman DB. A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes. Hum Mol Genet. 2019;28:1548–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 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  PubMed Central  Google Scholar 

  53. Barone R, Fiumara A, Jaeken J. Congenital disorders of glycosylation with emphasis on cerebellar involvement. Semin Neurol. 2014;34:357–66.

    PubMed  Google Scholar 

  54. Serrano M, de Diego V, Muchart J, Cuadras D, Felipe A, Macaya A, et al. Phosphomannomutase deficiency (PMM2-CDG): ataxia and cerebellar assessment. Orphanet J Rare Dis. 2015;10:138.

    PubMed  PubMed Central  Google Scholar 

  55. 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;33:2062–7.

    CAS  PubMed  Google Scholar 

  56. Goncalves FG, Freddi TAL, Taranath A, Lakshmanan R, Goetti R, Feltrin FS, et al. Tubulinopathies. Top Magn Reson Imaging. 2018;27:395–408.

    PubMed  Google Scholar 

  57. Arrigoni F, Romaniello R, Peruzzo D, Poretti A, Bassi MT, Pierpaoli C, et al. The spectrum of brainstem malformations associated to mutations of the tubulin genes family: MRI and DTI analysis. Eur Radiol. 2019;29:770–82.

    PubMed  Google Scholar 

  58. 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;137:1676–700.

    PubMed  Google Scholar 

  59. Wilker M, Christen HJ, Schuster S, Abicht A, Boltshauser E. VLDLR-associated Pontocerebellar hypoplasia with nonprogressive congenital Ataxia and a diagnostic neuroimaging pattern. Neuropediatrics. 2019;50:404–5.

    PubMed  Google Scholar 

  60. Valence S, Garel C, Barth M, Toutain A, Paris C, Amsallem D, et al. RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes. Clin Genet. 2016;90:545–9.

    CAS  PubMed  Google Scholar 

  61. Micalizzi A, Moroni I, Ginevrino M, Biagini T, Mazza T, Romani M, et al. Very mild features of dysequilibrium syndrome associated with a novel VLDLR missense mutation. Neurogenetics. 2016;17:191–5.

    CAS  PubMed  Google Scholar 

  62. Dehmel M, Brenner S, Suttorp M, Hahn G, Schutzle H, Dinger J, et al. Novel mutation in the DKC1 gene: neonatal Hoyeraal-Hreidarsson syndrome as a rare differential diagnosis in Pontocerebellar hypoplasia, primary microcephaly, and progressive bone marrow failure. Neuropediatrics. 2016;47:182–6.

    CAS  PubMed  Google Scholar 

  63. 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;64:573–82.

    CAS  PubMed  Google Scholar 

  64. Bönnemann CG, Wang CH, Quijano-Roy S, Deconinck N, Bertini E, Ferreiro A, et al. Diagnostic approach to the congenital muscular dystrophies. Neuromuscul Disord. 2014;24:289–311.

    PubMed  PubMed Central  Google Scholar 

  65. Rad A, Altunoglu U, Miller R, Maroofian R, James KN, Caglayan AO, et al. MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome). J Med Genet. 2019;56:332–9.

    CAS  PubMed  Google Scholar 

  66. Kayserili H, Altunoglu U, Yesil G, Rosti RO. Microcephaly, dysmorphic features, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds, and small cerebellum in four patients. Am J Med Genet A. 2016;170:1391–9.

    PubMed  Google Scholar 

  67. Dobyns WB, Aldinger KA, Ishak GE, Mirzaa GM, Timms AE, Grout ME, et al. MACF1 mutations encoding highly conserved zinc-binding residues of the GAR domain cause defects in neuronal migration and axon guidance. Am J Hum Genet. 2018;103:1009–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Tripathy R, Leca I, van Dijk T, Weiss J, van Bon BW, Sergaki MC, et al. Mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations. Neuron. 2018;100:1354–68 e1355.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Ravindran E, Hu H, Yuzwa SA, Hernandez-Miranda LR, Kraemer N, Ninnemann O, et al. Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation. PLoS Genet. 2017;13:e1006746.

    PubMed  PubMed Central  Google Scholar 

  70. Armstrong L, Biancheri R, Shyr C, Rossi A, Sinclair G, Ross CJ, et al. AIMP1 deficiency presents as a cortical neurodegenerative disease with infantile onset. Neurogenetics. 2014;15:157–9.

    CAS  PubMed  Google Scholar 

  71. Accogli A, Russell L, Sebire G, Riviere JB, St-Onge J, Addour-Boudrahem N, et al. Pathogenic variants in AIMP1 cause pontocerebellar hypoplasia. Neurogenetics. 2019;20:103–8.

    CAS  PubMed  Google Scholar 

  72. Hengel H, Magee A, Mahanjah M, Vallat JM, Ouvrier R, Abu-Rashid M, et al. CNTNAP1 mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis. Neurol Genet. 2017;3:e144.

    PubMed  PubMed Central  Google Scholar 

  73. Mancini GM, Schot R, de Wit MC, de Coo RF, Oostenbrink R, Bindels-de Heus K, et al. CSTB null mutation associated with microcephaly, early developmental delay, and severe dyskinesia. Neurology. 2016;86:877–8.

    PubMed  Google Scholar 

  74. van Dijk T, Barth P, Reneman L, Appelhof B, Baas F, Poll-The BT. A de novo missense mutation in the inositol 1,4,5-triphosphate receptor type 1 gene causing severe pontine and cerebellar hypoplasia: expanding the phenotype of ITPR1-related spinocerebellar ataxia’s. Am J Med Genet A. 2017;173:207–12.

    PubMed  Google Scholar 

  75. Wambach JA, Wegner DJ, Yang P, Shinawi M, Baldridge D, Betleja E, et al. Functional characterization of biallelic RTTN variants identified in an infant with microcephaly, simplified gyral pattern, pontocerebellar hypoplasia, and seizures. Pediatr Res. 2018;84:435–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Bindu PS, Nagappa M, Chiplunkar S, Govindaraj P, Mathuranath PS, Sinha S, et al. Clinical reasoning: West syndrome, pontocerebellar hypoplasia, and hypomyelination in a 6-month-old boy. Neurology. 2018;91:e1652–6.

    PubMed  Google Scholar 

  77. Cappuccio G, Pinelli M, Torella A, Vitiello G, D’Amico A, Alagia M, et al. An extremely severe phenotype attributed to WDR81 nonsense mutations. Ann Neurol. 2017;82:650–1.

    PubMed  Google Scholar 

  78. Stouffs K, Stergachis AB, Vanderhasselt T, Dica A, Janssens S, Vandervore L, et al. Expanding the clinical spectrum of biallelic ZNF335 variants. Clin Genet. 2018;94:246–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Yang CA, Chou IC, Cho DY, Lin CY, Huang HY, Ho YC, et al. Whole exome sequencing in Dandy-Walker variant with intellectual disability reveals an activating CIP2A mutation as novel genetic cause. Neurogenetics. 2018;19:157–63.

    CAS  PubMed  Google Scholar 

  80. 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;26:1659–67.

    PubMed  Google Scholar 

  81. Johnsen SD, Bodensteiner JB, Lotze TE. Frequency and nature of cerebellar injury in the extremely premature survivor with cerebral palsy. J Child Neurol. 2005;20:60–4.

    PubMed  Google Scholar 

  82. Zafeiriou DI, Ververi A, Anastasiou A, Soubasi V, Vargiami E. Pontocerebellar hypoplasia in extreme prematurity: clinical and neuroimaging findings. Pediatr Neurol. 2013;48:48–51.

    PubMed  Google Scholar 

  83. Poretti A, Boltshauser E, Doherty D. Cerebellar hypoplasia: differential diagnosis and diagnostic approach. Am J Med Genet C Semin Med Genet. 2014;166C:211–26.

    PubMed  Google Scholar 

  84. Severino M, Huisman T. Posterior fossa malformations. Neuroimaging Clin N Am. 2019;29:367–83.

    PubMed  Google Scholar 

  85. Joseph JT, Innes AM, Smith AC, Vanstone MR, Schwartzentruber JA, Bulman DE, et al. Neuropathologic features of pontocerebellar hypoplasia type 6. J Neuropathol Exp Neurol. 2014;73:1009–25.

    PubMed  Google Scholar 

  86. Correa DG, Ventura N, Gasparetto EL. Pontine hypoplasia in cri-du-chat syndrome: alterations in diffusion tensor imaging. Childs Nerv Syst. 2017;33:1241–2.

    PubMed  Google Scholar 

  87. Ninchoji T, Takanashi J. Pontine hypoplasia in 5p-syndrome: a key MRI finding for a diagnosis. Brain Dev. 2010;32:571–3.

    PubMed  Google Scholar 

  88. Poretti A, Boltshauser E. Checklist - Table 24. In: Boltshauser E, Schmahmann JD, editors. Cerebellar disorders in children. Cambridge: Mac Keith Press; 2012. p. 456.

    Google Scholar 

  89. Barth PG, Majoie CB, Caan MW, Weterman MA, Kyllerman M, Smit LM, et al. Pontine tegmental cap dysplasia: a novel brain malformation with a defect in axonal guidance. Brain. 2007;130:2258–66.

    PubMed  Google Scholar 

  90. Desai NK, Young L, Miranda MA, Kutz JW Jr, Roland PS, Booth TN. Pontine tegmental cap dysplasia: the neurotologic perspective. Otolaryngol Head Neck Surg. 2011;145:992–8.

    PubMed  Google Scholar 

  91. Blondiaux E, Valence S, Friszer S, Rodriguez D, Burglen L, Ducou le Pointe H, et al. Prenatal imaging findings of pontine tegmental cap dysplasia: report of four cases. Fetal Diagn Ther. 2019;45:197–204.

    PubMed  Google Scholar 

  92. Al-Shammari M, Al-Husain M, Al-Kharfy T, Alkuraya FS. A novel PTF1A mutation in a patient with severe pancreatic and cerebellar involvement. Clin Genet. 2011;80:196–8.

    CAS  PubMed  Google Scholar 

  93. 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 

  94. Vorona GA, Lanni SM. Fetal magnetic resonance imaging evaluation of a 21-week fetus with Zika virus infection. Pediatr Neurol. 2016;65:98–9.

    PubMed  Google Scholar 

  95. Wafik M, Taylor J, Lester T, Gibbons RJ, Shears DJ. 2 new cases of pontocerebellar hypoplasia type 10 identified by whole exome sequencing in a Turkish family. Eur J Med Genet. 2018;61:273–9.

    PubMed  Google Scholar 

  96. Glamuzina E, Brown R, Hogarth K, Saunders D, Russell-Eggitt I, Pitt M, et al. Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2. J Inherit Metab Dis. 2012;35:459–67.

    PubMed  Google Scholar 

  97. Ngo KJ, Rexach JE, Lee H, Petty LE, Perlman S, Valera JM, et al. A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders. Hum Mutat. 2019.

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Acknowledgments

We thank Prof. M. Steinlin for sharing imaging data of one patient. We thank P. Rüsch for his support in editing.

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Authors and Affiliations

  1. Department of Pediatric Neurology, University Children’s Hospital Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland

    Christina T. Rüsch, Bigna K. Bölsterli, Robert Steinfeld & Eugen Boltshauser

  2. Department of Diagnostic Imaging, University Children’s Hospital Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland

    Raimund Kottke

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  1. Christina T. Rüsch
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  2. Bigna K. Bölsterli
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Correspondence to Christina T. Rüsch.

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We would like to dedicate this article to Prof. P. G. Barth for his seminal contribution to the field.

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Rüsch, C.T., Bölsterli, B.K., Kottke, R. et al. Pontocerebellar Hypoplasia: a Pattern Recognition Approach. Cerebellum 19, 569–582 (2020). https://doi.org/10.1007/s12311-020-01135-5

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