The morphology of the cranium and the cervical vertebral column in patients with hypophosphatemic rickets PhD dissertation Hans Gjørup Department of Dentistry Health Aarhus University 2014 The morphology of the cranium and the cervical vertebral column in patients with hypophosphatemic rickets PhD dissertation Hans Gjørup Section of Pediatric Dentistry Department of Dentistry Health Aarhus University 2014 Content Preface .............................................................................................................................................. 4 List of original papers ........................................................................................................................ 7 List of abbreviations .......................................................................................................................... 8 1. Background ................................................................................................................................. 10 1.1. Rickets .................................................................................................................................. 10 1.1.1. Mineral metabolism and vitamin D ................................................................................. 10 1.1.2. Phosphate homeostasis and FGF23 ............................................................................. 10 1.1.3. Definition and classification ........................................................................................... 12 1.1.4. Hypophosphatemic rickets ............................................................................................. 15 1.1.5. Treatment of hypophosphatemic rickets ........................................................................ 16 1.2. Bone ..................................................................................................................................... 17 1.2.1. Bone formation .............................................................................................................. 18 1.2.2. Bone remodeling ............................................................................................................ 20 1.3. Craniofacial growth and development .................................................................................. 22 1.3.1. Normal versus pathologic development ......................................................................... 22 1.3.2. Prenatal development .................................................................................................... 22 1.3.3. Postnatal development .................................................................................................. 25 1.4. Craniofacial and cervical vertebral column morphology ....................................................... 27 1.4.1. Craniofacial morphology ................................................................................................ 27 1.4.2. Craniofacial morphology in HR patients ........................................................................ 27 1.4.3. Cervical vertebral column morphology .......................................................................... 29 1.5. Summary of introduction ...................................................................................................... 31 2. Aims and hypotheses .................................................................................................................. 32 2.1. Aims ..................................................................................................................................... 32 2.2. Hypotheses .......................................................................................................................... 33 3. Study population ......................................................................................................................... 34 3.1. Rickets patients .................................................................................................................... 34 3.2. Control group ........................................................................................................................ 36 4. Methods ...................................................................................................................................... 38 4.1. Radiological method ............................................................................................................. 38 4.2. Analyses of the cephalograms ............................................................................................. 38 4.2.1. Cephalometric analyses ................................................................................................ 38 1 4.2.2. Visual assessment of anatomical structures .................................................................. 42 4.2.3. Intra- and extra-cranial calcifications ............................................................................. 44 4.2.4. Reliability ....................................................................................................................... 44 4.3. Mineralizing enthesopathies ................................................................................................. 45 4.4. Medical treatment during childhood ..................................................................................... 45 4.5. Data management ................................................................................................................ 46 4.5.1. Paper I. Craniofacial morphology .................................................................................. 46 4.5.2. Paper II. Nasal bone and frontal sinus ........................................................................... 46 4.5.3. Paper III. Cervical spine ................................................................................................. 47 4.5.4. Paper IV. Intra- and extra-cranial calcifications ............................................................. 49 4.5.5. Morphology of the ST .................................................................................................... 49 5. Results ........................................................................................................................................ 51 5.1. Paper I. Craniofacial morphology ......................................................................................... 51 5.1.1. Endochondral-developed bone ...................................................................................... 52 5.1.2. Intramembraneous-developed bone .............................................................................. 52 5.2. Paper II. Nasal bone and frontal sinus ................................................................................. 53 5.2.1. Morphology and dimensions .......................................................................................... 53 5.2.2. Nasal bone morphology and HR severity ...................................................................... 54 5.3. Paper III. Cervical spine ....................................................................................................... 55 5.3.1. Cervical vertebrae morphology and dimensions ............................................................ 55 5.3.2. Cervical vertebral column and craniofacial structures ................................................... 56 5.3.3. Cervical vertebral column and HR severity .................................................................... 57 5.4. Paper IV. Intra- and extra-cranial calcifications .................................................................... 57 5.4.1. Cranial calcifications ...................................................................................................... 57 5.4.2. Cranial calcifications and HR severity ........................................................................... 59 5.4.3. Extra-skeletal calcifications and childhood treatment .................................................... 59 5.5. Sella turcica .......................................................................................................................... 60 5.5.1. ST morphology and dimensions .................................................................................... 60 5.5.2. ST and HR severity ........................................................................................................ 62 6. Discussion ................................................................................................................................... 63 6.1. Overall scope of the study .................................................................................................... 63 6.1.1. Design and composition of the study ............................................................................. 63 6.1.2. Assessment of morphology ........................................................................................... 65 6.1.3. Study population ............................................................................................................ 67 2 6.1.4. Methods of the study ..................................................................................................... 68 6.1.5. Biases of the study ........................................................................................................ 70 6.2. Discussion paper I-IV ........................................................................................................... 72 6.2.1. Paper I. Craniofacial morphology