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Journal of Pediatric Neurology 2024; 22(05): 366-376
DOI: 10.1055/s-0044-1786786
Review Article

Defects of Midbrain/Hindbrain Development: Defects of Anteroposterior and Dorsoventral Patterning

Arturo Biasco‡   *
1   Pediatrics Postgraduate Residency Program, University of Catania, Catania, Italy
,
Federica Dierna‡   *
1   Pediatrics Postgraduate Residency Program, University of Catania, Catania, Italy
,
Antonio Zanghì‡   *
2   Department of General Surgery and Medical-Surgical Specialty, University of Catania, Catania, Italy
,
Michele Vecchio
3   Rehabilitation Unit, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
,
Raffaele Falsaperla
4   Neonatology and Neonatal Intensive Care Unit, University Hospital Policlinico “G. Rodolico-San Marco,” Catania, Italy
,
Elena R. Praticò
5   Unit of Pediatrics, Carpi Hospital, Carpi, Italy
,
Antonino Maniaci
6   Chair of Othorhinolaryngology, Department of Medicine and Surgery, Kore University, Enna, Italy
,
Martino Ruggieri
7   Unit of Clinical Pediatrics, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Agata Polizzi
8   Chair of Othorhinolaryngology, Department of Educational Sciences, University of Catania, Catania, Italy
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Abstract

The knowledge regarding the midbrain and the hindbrain (MBHB) malformations has been progressively increased in recent years, thanks to the advent of neuroimaging and genetic technologies. Many classifications have been proposed in order to well describe all of these patterns. The most complete and detailed one is based on the genetic and embryologic features that allow an easier and effective knowledge of these disturbs. It categorizes them into four primary groups: (1) Malformations resulting from early anteroposterior and dorsoventral patterning defects or the misspecification of MBHB germinal zones.(2) Malformations linked to later generalized developmental disorders that notably impact the brain stem and cerebellum, with a pathogenesis that is at least partially comprehended.(3) Localized brain malformations significantly affecting the brain stem and cerebellum, with a pathogenesis that is partly or largely understood, encompassing local proliferation, migration, and axonal guidance.(4) Combined hypoplasia and atrophy observed in presumed prenatal-onset degenerative disorders. Regarding diagnosis, brain stem malformations are typically identified during prenatal assessments, particularly when they are linked with anomalies in the cerebellum and cerebrum. Magnetic resonance imaging is the primary neuroimaging method in the evaluation of these malformations. The clinical characteristics of individuals with malformations in the midbrain or hindbrain are generally nonspecific. Common findings at presentation are hypotonia, motor retardation, ataxia, variable degree of intellectual disability, and abnormal eye movement (e.g., nystagmus, abnormal saccades, oculomotor apraxia, strabismus, and abnormal smooth pursuit). The complexity and the number of these MBHB malformations are constantly increasing. We will provide an overview of MBHB disorders, focusing on embryology, genetic, clinical, and neuroradiology features that could be helpful for clinicians and neuroscientist to understand process of these conditions.

Keywords

midbrain malformations - genetics - anteroposterior - dorsoventral - patterning - neurons

* These authors contributed equally to this article.




Publication History

Received: 11 December 2023

Accepted: 03 April 2024

Article published online:
29 May 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Doherty D, Millen KJ, Barkovich AJ. Midbrain and hindbrain malformations: advances in clinical diagnosis, imaging, and genetics. Lancet Neurol 2013; 12 (04) 381-393
    CrossrefPubMedGoogle Scholar
  • 2 Barbagallo M, Ruggieri M, Incorpora G. et al. Infantile spasms in the setting of Sturge-Weber syndrome. Childs Nerv Syst 2009; 25 (01) 111-118
    CrossrefPubMedGoogle Scholar
  • 3 Barkovich AJ, Millen KJ, Dobyns WB. A developmental and genetic classification for midbrain-hindbrain malformations. Brain 2009; 132 (Pt 12): 3199-3230
    CrossrefPubMedGoogle Scholar
  • 4 Vincent A, Jacobson L, Plested P. et al. Antibodies affecting ion channel function in acquired neuromyotonia, in seropositive and seronegative myasthenia gravis, and in antibody-mediated arthrogryposis multiplex congenita. Ann N Y Acad Sci 1998; 841: 482-496
    CrossrefPubMedGoogle Scholar
  • 5 Parisi MA, Dobyns WB. Human malformations of the midbrain and hindbrain: review and proposed classification scheme. Mol Genet Metab 2003; 80 (1-2): 36-53
    CrossrefPubMedGoogle Scholar
  • 6 Leuzzi V, Mastrangelo M, Polizzi A. et al. Report of two never treated adult sisters with aromatic L-amino acid decarboxylase deficiency: a portrait of the natural history of the disease or an expanding phenotype?. JIMD Rep 2015; 15: 39-45
    PubMedGoogle Scholar
  • 7 Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB. A developmental and genetic classification for malformations of cortical development. Neurology 2005; 65 (12) 1873-1887
    CrossrefPubMedGoogle Scholar
  • 8 Ruggieri M, Polizzi A. From Aldrovandi's “Homuncio” (1592) to Buffon's girl (1749) and the “Wart Man” of Tilesius (1793): antique illustrations of mosaicism in neurofibromatosis?. J Med Genet 2003; 40 (03) 227-232
    CrossrefPubMedGoogle Scholar
  • 9 Patel S, Barkovich AJ. Analysis and classification of cerebellar malformations. AJNR Am J Neuroradiol 2002; 23 (07) 1074-1087
    PubMedGoogle Scholar
  • 10 Ruggieri M, Praticò AD, Serra A. et al. Early history of neurofibromatosis type 2 and related forms: earliest descriptions of acoustic neuromas, medical curiosities, misconceptions, landmarks and the pioneers behind the eponyms. Childs Nerv Syst 2017; 33 (04) 549-560
    CrossrefPubMedGoogle Scholar
  • 11 Abdel Razek AA, Castillo M. Magnetic resonance imaging of malformations of midbrain-hindbrain. J Comput Assist Tomogr 2016; 40 (01) 14-25
    CrossrefPubMedGoogle Scholar
  • 12 Pavone P, Briuglia S, Falsaperla R. et al. Wide spectrum of congenital anomalies including choanal atresia, malformed extremities, and brain and spinal malformations in a girl with a de novo 5.6-Mb deletion of 13q12.11-13q12.13. Am J Med Genet A 2014; 164A (07) 1734-1743
    CrossrefPubMedGoogle Scholar
  • 13 Barkovich AJ, Millen KJ, Dobyns WB. A developmental classification of malformations of the brainstem. Ann Neurol 2007; 62 (06) 625-639
    CrossrefPubMedGoogle Scholar
  • 14 Pavone P, Praticò AD, Ruggieri M, Falsaperla R. Hypomelanosis of Ito: a round on the frequency and type of epileptic complications. Neurol Sci 2015; 36 (07) 1173-1180
    CrossrefPubMedGoogle Scholar
  • 15 Poretti A, Boltshauser E, Plecko B. Brainstem disconnection: case report and review of the literature. Neuropediatrics 2007; 38 (04) 210-212
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Pavone P, Praticò AD, Ruggieri M. et al. Acquired peripheral neuropathy: a report on 20 children. Int J Immunopathol Pharmacol 2012; 25 (02) 513-517
    CrossrefPubMedGoogle Scholar
  • 17 Caminero F, Cascella M. Neuroanatomy, mesencephalon midbrain. October 24, 2022. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023
    Google Scholar
  • 18 Pavone V, Signorelli SS, Praticò AD. et al. Total hemi-overgrowth in pigmentary mosaicism of the (hypomelanosis of) Ito type: eight case reports. Medicine (Baltimore) 2016; 95 (10) e2705
    CrossrefPubMedGoogle Scholar
  • 19 Alkan O, Kizilkilic O, Yildirim T. Malformations of the midbrain and hindbrain: a retrospective study and review of the literature. Cerebellum 2009; 8 (03) 355-365
    CrossrefPubMedGoogle Scholar
  • 20 Pratico AD, Ruggieri M, Falsaperla R, Pavone P. A probable topiramate-induced limbs paraesthesia and rigid fingers flexion. Curr Drug Saf 2018; 13 (02) 131-136
    CrossrefPubMedGoogle Scholar
  • 21 Chambers D, Wilson LJ, Alfonsi F. et al. Rhombomere-specific analysis reveals the repertoire of genetic cues expressed across the developing hindbrain. Neural Dev 2009; 4: 6
    CrossrefPubMedGoogle Scholar
  • 22 Pavone P, Praticò AD, Gentile G. et al. A neurocutaneous phenotype with paired hypo- and hyperpigmented macules, microcephaly and stunted growth as prominent features. Eur J Med Genet 2016; 59 (05) 283-289
    CrossrefPubMedGoogle Scholar
  • 23 Lim Y, Golden JA. Patterning the developing diencephalon. Brain Res Brain Res Rev 2007; 53 (01) 17-26
    CrossrefPubMedGoogle Scholar
  • 24 Pavone P, Nigro F, Falsaperla R. et al. Hemihydranencephaly: living with half brain dysfunction. Ital J Pediatr 2013; 39: 3
    CrossrefPubMedGoogle Scholar
  • 25 Bermingham NA, Hassan BA, Wang VY. et al. Proprioceptor pathway development is dependent on Math1. Neuron 2001; 30 (02) 411-422
    CrossrefPubMedGoogle Scholar
  • 26 Ruggieri M, Polizzi A, Marceca GP, Catanzaro S, Praticò AD, Di Rocco C. Introduction to phacomatoses (neurocutaneous disorders) in childhood. Childs Nerv Syst 2020; 36 (10) 2229-2268
    CrossrefPubMedGoogle Scholar
  • 27 Yamada M, Terao M, Terashima T. et al. Origin of climbing fiber neurons and their developmental dependence on Ptf1a. J Neurosci 2007; 27 (41) 10924-10934
    CrossrefPubMedGoogle Scholar
  • 28 Incorpora G, Pavone P, Castellano-Chiodo D, Praticò AD, Ruggieri M, Pavone L. Gelastic seizures due to hypothalamic hamartoma: rapid resolution after endoscopic tumor disconnection. Neurocase 2013; 19 (05) 458-461
    CrossrefPubMedGoogle Scholar
  • 29 Jissendi-Tchofo P, Severino M, Nguema-Edzang B, Toure C, Soto Ares G, Barkovich AJ. Update on neuroimaging phenotypes of mid-hindbrain malformations. Neuroradiology 2015; 57 (02) 113-138
    CrossrefPubMedGoogle Scholar
  • 30 Ruggieri M, Praticò AD, Caltabiano R, Polizzi A. Rediagnosing one of Smith's patients (John McCann) with “neuromas tumours” (1849). Neurol Sci 2017; 38 (03) 493-499
    CrossrefPubMedGoogle Scholar
  • 31 Nakamura H, Watanabe Y. Isthmus organizer and regionalization of the mesencephalon and metencephalon. Int J Dev Biol 2005; 49 (2-3): 231-235
    CrossrefPubMedGoogle Scholar
  • 32 Palano GM, Praticò AD, Praticò ER. et al. Intossicazione accidentale da alcol etilico in un lattante di 30 giorni. Quadro clinico e follow-up neurologico. Minerva Pediatr 2007; 59 (03) 275-279
    PubMedGoogle Scholar
  • 33 Waters ST, Lewandoski M. A threshold requirement for Gbx2 levels in hindbrain development. Development 2006; 133 (10) 1991-2000
    CrossrefPubMedGoogle Scholar
  • 34 Leonardi S, Praticò AD, Lionetti E, Spina M, Vitaliti G, La Rosa M. Intramuscular vs intradermal route for hepatitis B booster vaccine in celiac children. World J Gastroenterol 2012; 18 (40) 5729-5733
    CrossrefPubMedGoogle Scholar
  • 35 Sgaier SK, Millet S, Villanueva MP, Berenshteyn F, Song C, Joyner AL. Morphogenetic and cellular movements that shape the mouse cerebellum; insights from genetic fate mapping. Neuron 2005; 45 (01) 27-40
    PubMedGoogle Scholar
  • 36 Fiumara A, Lanzafame G, Arena A. et al. COVID-19 pandemic outbreak and its psychological impact on patients with rare lysosomal diseases. J Clin Med 2020; 9 (09) 2716
    CrossrefPubMedGoogle Scholar
  • 37 Lenroot RK, Giedd JN. Brain development in children and adolescents: insights from anatomical magnetic resonance imaging. Neurosci Biobehav Rev 2006; 30 (06) 718-729
    CrossrefPubMedGoogle Scholar
  • 38 Salafia S, Praticò AD, Pizzo E, Greco F, Di Bella D. Hemiconvulsion-hemiplegia-epilepsy syndrome. Magnetic resonance findings in a 3-year-old boy. Neurol Neurochir Pol 2013; 47 (06) 584-589
    CrossrefPubMedGoogle Scholar
  • 39 Sehgal V, Delproposto Z, Haddar D. et al. Susceptibility-weighted imaging to visualize blood products and improve tumor contrast in the study of brain masses. J Magn Reson Imaging 2006; 24 (01) 41-51
    CrossrefPubMedGoogle Scholar
  • 40 Praticò AD, Leonardi S. Immunotherapy for food allergies: a myth or a reality?. Immunotherapy 2015; 7 (02) 147-161
    CrossrefPubMedGoogle Scholar
  • 41 Keser Z, Hasan KM, Mwangi BI. et al. Diffusion tensor imaging of the human cerebellar pathways and their interplay with cerebral macrostructure. Front Neuroanat 2015; 9: 41
    CrossrefPubMedGoogle Scholar
  • 42 Ruggieri M, Polizzi A, Catanzaro S, Bianco ML, Praticò AD, Di Rocco C. Neurocutaneous melanocytosis (melanosis). Childs Nerv Syst 2020; 36 (10) 2571-2596
    CrossrefPubMedGoogle Scholar
  • 43 Sellick GS, Barker KT, Stolte-Dijkstra I. et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 2004; 36 (12) 1301-1305
    CrossrefPubMedGoogle Scholar
  • 44 Praticò AD, Ruggieri M. COVID-19 vaccination for children: may be necessary for the full eradication of the disease. Pediatr Res 2021; 90 (06) 1102-1103
    CrossrefPubMedGoogle Scholar
  • 45 Hoshino M, Nakamura S, Mori K. et al. Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum. Neuron 2005; 47 (02) 201-213
    CrossrefPubMedGoogle Scholar
  • 46 Praticò AD, Mistrello G, La Rosa M. et al. Immunotherapy: a new horizon for egg allergy?. Expert Rev Clin Immunol 2014; 10 (05) 677-686
    CrossrefPubMedGoogle Scholar
  • 47 Al-Baradie R, Yamada K, St Hilaire C. et al. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet 2002; 71 (05) 1195-1199
    CrossrefPubMedGoogle Scholar
  • 48 Praticò AD, Giallongo A, Arrabito M. et al. SCN2A and its related epileptic phenotypes. Journal of Pediatric Neurology 2023; 21 (03) 173-185
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Michielse CB, Bhat M, Brady A. et al. Refinement of the locus for hereditary congenital facial palsy on chromosome 3q21 in two unrelated families and screening of positional candidate genes. Eur J Hum Genet 2006; 14 (12) 1306-1312
    CrossrefPubMedGoogle Scholar
  • 50 Praticò AD, Falsaperla R, Comella M, Belfiore G, Polizzi A, Ruggieri M. Case report: A gain-of-function of hamartin may lead to a distinct “inverse TSC1-hamartin” phenotype characterized by reduced cell growth. Front Pediatr 2023; 11: 1101026
    CrossrefPubMedGoogle Scholar
  • 51 Glasgow SM, Henke RM, Macdonald RJ, Wright CV, Johnson JE. Ptf1a determines GABAergic over glutamatergic neuronal cell fate in the spinal cord dorsal horn. Development 2005; 132 (24) 5461-5469
    CrossrefPubMedGoogle Scholar
  • 52 Praticò AD. COVID-19 pandemic for Pediatric Health Care: disadvantages and opportunities. Pediatr Res 2021; 89 (04) 709-710
    CrossrefPubMedGoogle Scholar
  • 53 Sotelo C. Cellular and genetic regulation of the development of the cerebellar system. Prog Neurobiol 2004; 72 (05) 295-339
    CrossrefPubMedGoogle Scholar
  • 54 Ruggieri M, Milone P, Pavone P. et al. Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients. Am J Med Genet A 2012; 158A (11) 2870-2880
    CrossrefPubMedGoogle Scholar
  • 55 Kenney AM, Cole MD, Rowitch DH. Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development 2003; 130 (01) 15-28
    CrossrefPubMedGoogle Scholar
  • 56 Ruggieri M, Iannetti P, Clementi M. et al. Neurofibromatosis type 1 and infantile spasms. Childs Nerv Syst 2009; 25 (02) 211-216
    CrossrefPubMedGoogle Scholar
  • 57 Kaindl AM, Asimiadou S, Manthey D, Hagen MV, Turski L, Ikonomidou C. Antiepileptic drugs and the developing brain. Cell Mol Life Sci 2006; 63 (04) 399-413
    CrossrefPubMedGoogle Scholar
  • 58 Ruggieri M, Pavone V, De Luca D, Franzò A, Tiné A, Pavone L. Congenital bone malformations in patients with neurofibromatosis type 1 (Nf1). J Pediatr Orthop 1999; 19 (03) 301-305
    CrossrefPubMedGoogle Scholar
  • 59 Takano T, Akahori S, Takeuchi Y, Ohno M. Neuronal apoptosis and gray matter heterotopia in microcephaly produced by cytosine arabinoside in mice. Brain Res 2006; 1089 (01) 55-66
    CrossrefPubMedGoogle Scholar
  • 60 Ruggieri M, Huson SM. The neurofibromatoses. An overview. Ital J Neurol Sci 1999; 20 (02) 89-108
    CrossrefPubMedGoogle Scholar
  • 61 Sarnat HB, Benjamin DR, Siebert JR, Kletter GB, Cheyette SR. Agenesis of the mesencephalon and metencephalon with cerebellar hypoplasia: putative mutation in the EN2 gene–report of 2 cases in early infancy. Pediatr Dev Pathol 2002; 5 (01) 54-68
    CrossrefPubMedGoogle Scholar
  • 62 Ruggieri M. Cutis tricolor: congenital hyper- and hypopigmented lesions in a background of normal skin with and without associated systemic features: further expansion of the phenotype. Eur J Pediatr 2000; 159 (10) 745-749
    CrossrefPubMedGoogle Scholar
  • 63 Bednarek N, Scavarda D, Mesmin F, Sabouraud P, Motte J, Morville P. Midbrain disconnection: an aetiology of severe central neonatal hypotonia. Eur J Paediatr Neurol 2005; 9 (06) 419-422
    CrossrefPubMedGoogle Scholar
  • 64 Pratico AD, Longo L, Mansueto S. et al. Off-label use of drugs and adverse drug reactions in pediatric units: a prospective, multicenter study. Curr Drug Saf 2018; 13 (03) 200-207
    CrossrefPubMedGoogle Scholar
  • 65 McCann E, Pilling D, Hesseling M, Roberts D, Subhedar N, Sweeney E. Pontomedullary disconnection: fetal and neonatal considerations. Pediatr Radiol 2005; 35 (08) 812-814
    CrossrefPubMedGoogle Scholar
  • 66 Ruggieri M, Polizzi A, Pavone L, Musumeci S. Thalamic syndrome in children with measles infection and selective, reversible thalamic involvement. Pediatrics 1998; 101 (1 Pt 1): 112-119
    CrossrefPubMedGoogle Scholar
  • 67 Duffield C, Jocson J, Wootton-Gorges SL. Brainstem disconnection. Pediatr Radiol 2009; 39 (12) 1357-1360
    CrossrefPubMedGoogle Scholar
  • 68 Ruggieri M, Iannetti P, Pavone L. Delineation of a newly recognized neurocutaneous malformation syndrome with “cutis tricolor”. Am J Med Genet A 2003; 120A (01) 110-116
    CrossrefPubMedGoogle Scholar
  • 69 Lumsden A. Segmentation and compartition in the early avian hindbrain. Mech Dev 2004; 121 (09) 1081-1088
    CrossrefPubMedGoogle Scholar
  • 70 Pavone P, Praticò AD, Pavone V. et al. Ataxia in children: early recognition and clinical evaluation. Ital J Pediatr 2017; 43 (01) 6
    CrossrefPubMedGoogle Scholar
  • 71 Cordes SP. Molecular genetics of cranial nerve development in mouse. Nat Rev Neurosci 2001; 2 (09) 611-623
    CrossrefPubMedGoogle Scholar
  • 72 Stoodley CJ. The cerebellum and neurodevelopmental disorders. Cerebellum 2016; 15 (01) 34-37
    CrossrefPubMedGoogle Scholar
  • 73 Schneider-Maunoury S, Seitanidou T, Charnay P, Lumsden A. Segmental and neuronal architecture of the hindbrain of Krox-20 mouse mutants. Development 1997; 124 (06) 1215-1226
    CrossrefPubMedGoogle Scholar
  • 74 Bosley TM, Alorainy IA, Salih MA. et al. The clinical spectrum of homozygous HOXA1 mutations. Am J Med Genet A 2008; 146A (10) 1235-1240
    CrossrefPubMedGoogle Scholar
  • 75 Bosley TM, Salih MA, Alorainy IA. et al. Clinical characterization of the HOXA1 syndrome BSAS variant. Neurology 2007; 69 (12) 1245-1253
    CrossrefPubMedGoogle Scholar
  • 76 Chan WM, Traboulsi EI, Arthur B, Friedman N, Andrews C, Engle EC. Horizontal gaze palsy with progressive scoliosis can result from compound heterozygous mutations in ROBO3. J Med Genet 2006; 43 (03) e11
    CrossrefPubMedGoogle Scholar
  • 77 Chiaramonte R, Pavone P, Vecchio M. Speech rehabilitation in dysarthria after stroke: a systematic review of the studies. Eur J Phys Rehabil Med 2020; 56 (05) 547-562
    CrossrefPubMedGoogle Scholar
  • 78 Chiaramonte R, Vecchio M. Dysarthria and stroke. The effectiveness of speech rehabilitation. A systematic review and meta-analysis of the studies. Eur J Phys Rehabil Med 2021; 57 (01) 24-43
    CrossrefPubMedGoogle Scholar
  • 79 Chiaramonte R, Vecchio M. A systematic review of measures of dysarthria severity in stroke patients. PM R 2021; 13 (03) 314-324
    CrossrefPubMedGoogle Scholar
  • 80 Vecchio M, Gracies JM, Panza F. et al. Change in coefficient of fatigability following rapid, repetitive movement training in post-stroke spastic paresis: a prospective open-label observational study. J Stroke Cerebrovasc Dis 2017; 26 (11) 2536-2540
    CrossrefPubMedGoogle Scholar
  • 81 Nakano M, Yamada K, Fain J. et al. Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet 2001; 29 (03) 315-320
    CrossrefPubMedGoogle Scholar
  • 82 Zaki MS, Saleem SN, Dobyns WB. et al. Diencephalic-mesencephalic junction dysplasia: a novel recessive brain malformation. Brain 2012; 135 (Pt 8): 2416-2427
    CrossrefPubMedGoogle Scholar