321 H.J. ten Donkelaar et al., Clinical Neuroembryology, DOI 10.1007/978-3-642-54687-7_7, © Springer-Verlag Berlin Heidelberg 2014 7.1 Introduction The brain stem is composed of the midbrain (the mesencepha- lon) and the hindbrain (the rhombencephalon), and is, at least during development, segmentally organized. The midbrain is composed of two temporarily present segments known as mesomeres, whereas the hindbrain is composed of eight, also temporarily present, rhombomeres (Fig. 7.1). More recently, 12 rhombomeres were distinguished (Chap. 2). The cerebel- lum largely arises from the first rhombomere (Chap. 8). The brain stem contains the reticular formation which is involved in the control of respiration, circulation, wakefulness and locomotion. The brain stem also contributes 10 of the 12 pairs of cranial nerves, III-XII. The motor nuclei for the extraocu- lar muscles arise from mesomere 1 (the oculomotor nucleus), the isthmic rhombomere (the trochlear nucleus) and rhombo- mere 5 (the abducens nucleus). The motor nuclei of the cra- nial nerves, innervating the branchial arch musculature, arise from the second, fourth, sixth and seventh rhombomeres. The neural crest, flanking the developing rhombencephalon, makes important contributions to the branchial arches (Chap. 5). A great number of genes are involved in the proper devel- opment of the brain stem (Cordes 2001; Moens and Prince 2002; Guthrie 2007; Sambasivan et al. 2011). The isthmus organizer regulates the early development of the mesencepha- lon and of the rostral part of the rhombencephalon (Wurst and Bally-Cuif 2001; Joyner 2002). Mutations of genes involved such as Otx2, En1 and En2 result in extensive defects in the midbrain, the cerebellum and the pons. Each rhombomere is characterized by a unique combination of Hox genes, its Hox code. In mice, spontaneous and targeted (knockout) mutations Development and Developmental Disorders of the Brain Stem Hans J. ten Donkelaar, Johannes R.M. Cruysberg, Ronald Pennings, and Martin Lammens 7 H.J. ten Donkelaar, M.D., Ph.D. () 935 Department of Neurology, Radboud University Nijmegen Medical Centre, 9101, Nijmegen 6500 HB, The Netherlands e-mail: hans.tendonkelaar@radboudumc.nl, hjtendonkelaar@gmail.com J.R.M. Cruysberg, M.D., Ph.D. Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands R. Pennings, M.D., Ph.D. 377 Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, 9101, Nijmegen 6500 HB, The Netherlands M. Lammens, M.D., Ph.D. Department of Pathology, University Hospital Antwerpen, Wilrijkstraat 10, Edegem B-2650, Belgium Contents 7.1 Introduction ..................................................................... 321 7.2 Pattern Formation and Segmentation of the Brain Stem............................................................. 323 7.2.1 Pattern Formation of the Brain Stem................................. 323 Clinical Case 7.1. Agenesis of the Mesencephalon and Metencephalon with Cerebellar Hypoplasia .............. 326 7.2.2 Segmentation of the Brain Stem........................................ 327 7.3 Development and Developmental Disorders of the Cranial Nerves ...................................................... 329 7.3.1 Development of the Cranial Nerves and Their Nuclei in Rodents ............................................. 329 7.3.2 Development of Cranial Nerve Ganglia in Rodents.......... 331 7.3.3 Developmental and Developmental Disorders of the Human Cranial Nerves ............................................ 331 7.3.4 Congenital Cranial Dysinnervation Disorders .................. 332 Clinical Case 7.2. Congenital Cranial Dysinnervation Disorders ........................................................................... 339 Clinical Case 7.3. Congenital Facial Palsy ....................... 340 Clinical Case 7.4. Möbius Syndrome................................ 341 7.3.5 The Sudden Infant Death Syndrome ................................. 343 7.4 Development of the Auditory System ............................ 343 7.4.1 Development of the Ear..................................................... 344 7.4.2 Development of the Auditory Projections ......................... 349 7.4.3 Developmental Disorders of the Auditory System............ 350 Clinical Case 7.5. Pendred Syndrome ............................... 352 7.4.4 Mutated Genes Involved in Deafness ................................ 353 Clinical Case 7.6. Branchio-oto-renal Syndrome ............. 359 Clinical Case 7.7. Usher Syndrome .................................. 361 References .................................................................................... 362