Emery & Rimoin's Principles and Practice of Medical Genetics

PREFACE......Page 3
FOREWORD......Page 5
PERSONAL MEMORIES OF DAVID RIMOIN......Page 7
Basic Principles......Page 9
1.2 INTRODUCTION......Page 11
1.3 FOUNDATIONS OF MEDICAL GENETICS BEFORE 1956......Page 12
1.4 GROWTH AND DEVELOPMENT OF MEDICAL GENETICS: 1956 TO THE PRESENT......Page 18
1.5 THE FUTURE......Page 38
1.6 ADDENDUM (PSH)......Page 39
1.7 A TIMELINE FOR MEDICAL GENETICS......Page 41
REFERENCES......Page 45
FURTHER READING......Page 48
2.1 INTRODUCTION......Page 50
2.2 THE PRINCIPLES OF DISEASE......Page 51
2.3 DEFINING DISEASE......Page 52
2.4 THE HOW QUESTIONS......Page 53
2.6 THE WHY QUESTIONS......Page 58
2.7 PREVENTION AND TREATMENT......Page 61
2.8 CONCLUSION......Page 63
REFERENCES......Page 64
3.2 FREQUENCY OF GENETIC DISEASE......Page 67
3.3 MORBIDITY AND MORTALITY DUE TO GENETIC DISEASE......Page 69
REFERENCES......Page 70
4.2 GENOMICS......Page 71
4.3 MAPPING THE HUMAN GENOME......Page 72
4.5 CURRENT APPORACHES TO SEQUENCE PARTS OR THE WHOLE HUMAN GENOME......Page 74
4.6 AN APPROACH FOR CLONING HUMAN DISEASE GENES......Page 76
4.7 SEQUENCE-BASED METHODS FOR DETECTING CHROMOSOMAL ABNORMALITIES......Page 77
4.8 PROTEOMICS......Page 78
REFERENCES......Page 79
5.2 DOUBLE HELIX STRUCTURE, DNA REPLICATION, TRANSCRIPTION, AND MEIOTIC RECOMBINATION......Page 81
5.3 ORGANIZATION OF GENOMIC DNA......Page 83
5.4 GENE STRUCTURE AND THE MOLECULAR PATHWAY OF GENE EXPRESSION......Page 86
REFERENCES......Page 95
6.2 EPIGENETIC MECHANISMS: CHROMATIN, DNA METHYLATION AND LONG NONCODING RNAs......Page 97
6.3 EPIGENETIC REPROGRAMMING......Page 100
6.4 EPIGENETIC REGULATION OF X INACTIVATION......Page 101
6.5 GENOMIC IMPRINTING......Page 103
6.6 GENETIC DISORDERS DUE TO GENES AFFECTING CHROMATIN STRUCTURE......Page 109
6.8 CANCER EPIGENETICS......Page 112
6.10 ABNORMALITIES IN EPIGENETIC PROGRAMMING LINKED TO INFERTILITY AND ASSISTED REPRODUCTION......Page 114
6.12 GENETIC–EPIGENETIC INTERACTIONS......Page 115
REFERENCES......Page 116
WEBSITES......Page 125
7.1 INTRODUCTION......Page 129
7.2 MOLECULAR MECHANISMS OF MUTATION CAUSING HUMAN INHERITED DISEASE......Page 130
7.3 DISEASE-CAUSING MUTATIONS......Page 132
7.4 CONSEQUENCES OF MUTATIONS......Page 149
7.5 GENERAL PRINCIPLES OF GENOTYPE–PHENOTYPE CORRELATIONS......Page 164
7.6 WHY STUDY MUTATION?......Page 165
REFERENCES......Page 166
FURTHER READING......Page 175
8.2 PEDIGREE CONSTRUCTION......Page 177
8.3 UNIFACTORIAL INHERITANCE/ SINGLE-GENE DISORDERS......Page 178
8.4 DOMINANCE AND RECESSIVENESS......Page 179
8.5 AUTOSOMAL-DOMINANT INHERITANCE......Page 181
8.6 AUTOSOMAL RECESSIVE INHERITANCE......Page 183
8.8 X-LINKED RECESSIVE INHERITANCE......Page 186
8.9 X-LINKED DOMINANT INHERITANCE......Page 188
8.11 PARTIAL SEX LINKAGE......Page 189
REFERENCES......Page 193
9.1 INTRODUCTION TO LINKAGE ANALYSIS......Page 195
9.2 LINKAGE ANALYSIS: BASIC CONCEPTS......Page 196
9.3 EXTENDING PARAMETRIC LINKAGE ANALYSIS......Page 199
9.4 LINKAGE ANALYSIS FOR COMPLEX AND QUANTITATIVE TRAITS......Page 200
9.5 LINKAGE ANALYSIS: FUTURE DIRECTIONS......Page 201
FURTHER READING......Page 202
10.2 CHROMOSOME STRUCTURE......Page 204
10.3 CHROMOSOMES IN CELL DIVISION......Page 206
10.4 METHODS FOR STUDYING HUMAN CHROMOSOMES......Page 210
10.5 FUNCTIONAL ORGANIZATION OF CHROMOSOMES......Page 217
10.6 SEX CHROMOSOMES AND SEX DETERMINATION......Page 220
10.7 UNIPARENTAL DISOMY AND IMPRINTING......Page 222
10.8 CHROMOSOME ABNORMALITIES......Page 223
GLOSSARY......Page 225
REFERENCES......Page 226
ABBREVIATIONS......Page 230
11.1 MITOCHONDRIAL BIOLOGY AND GENETICS......Page 232
11.2 INHERITED NDNA MITOCHONDRIAL DISEASES......Page 293
11.3 MITOCHONDRIAL ETIOLOGY FOR COMMON METABOLIC AND VISCERAL DISEASES......Page 303
11.4 MITOCHONDRIAL ETIOLOGY FOR NEURODEGENERATIVE DISEASES......Page 305
11.5 MITOCHONDRIAL DEFECTS IN CANCER......Page 319
11.6 THERAPEUTIC APPROACHES TO MITOCHONDRIAL DISEASE......Page 322
11.7 A MITOCHONDRIAL PARADIGM FOR COMPLEX DISEASE......Page 327
REFERENCES......Page 329
FURTHER READING......Page 381
12.2 DEFINITIONS AND TERMINOLOGY......Page 383
12.3 DETERMINING THE GENETIC COMPONENT OF A TRAIT......Page 385
12.5 GENOME-WIDE ASSOCIATION STUDIES......Page 389
12.6 ASSOCIATION METHODS/ STATISTICAL ANALYSIS......Page 391
12.7 ANALYSIS OF RARE VARIANTS USING NEW TECHNOLOGIES......Page 392
REFERENCES......Page 393
13.2 HARDY–WEINBERG LAW......Page 398
13.3 FACTORS THAT AFFECT HARDY– WEINBERG EQUILIBRIUM......Page 402
13.4 APPLICATIONS IN POPULATION GENETICS......Page 407
FURTHER READING......Page 409
14.1 INTRODUCTION......Page 410
14.3 PHYSIOLOGIC HOMEOSTASIS......Page 411
14.5 ONTOGENESIS OF ANATOMIC STRUCTURES: ANGULAR HOMEOSTASIS......Page 413
14.6 PATHOGENETICS OF REFINED TRAITS......Page 415
14.7 PATHWAYS AND MULTIPLE-STAGE PROCESSES......Page 416
14.8 MOLECULAR PATHOGENETICS......Page 418
14.9 CONCLUSIONS......Page 420
REFERENCES......Page 421
15.1 INTRODUCTION AND OVERVIEW......Page 423
15.3 THE CONCEPT OF DEVELOPMENTAL FIELDS AND FIELD DEFECTS......Page 424
15.4 CELLULAR SIGNALING IN DEVELOPMENT: THE CONCEPTS OF INDUCTION AND COMPETENCE......Page 426
15.6 STEPS AND CONCEPTS IN EMBRYONIC DEVELOPMENT......Page 428
15.7 REGULATION OF GENE EXPRESSION IN DEVELOPMENT......Page 439
15.8 DEVELOPMENTAL GENE PATHWAYS AND FAMILIES......Page 448
15.9 ORGANOGENESIS......Page 458
REFERENCES......Page 475
16.2 DETERMINING ZYGOSITY......Page 486
16.6 TWINS IN GENETIC STUDIES......Page 487
16.7 DIZYGOTIC TWINS......Page 488
16.8 MONOZYGOTIC TWINS......Page 490
REFERENCES......Page 495
17.1 INTRODUCTION......Page 506
17.2 A GENETIC BASIS OF CANCER......Page 507
17.3 VIRAL ONCOGENES......Page 508
17.4 ONCOGENIC ALLELES IN HUMAN CANCERS......Page 509
17.5 TUMOR SUPPRESSOR GENES......Page 515
17.6 THE ROLE OF DNA DAMAGE REPAIR GENES IN INHERITED CANCER SYNDROMES......Page 533
REFERENCES......Page 544
18.2 WHAT IS AGING?......Page 550
18.3 WHY DO WE AGE?......Page 553
18.4 HOW DO WE AGE?......Page 557
18.5 PROGEROID SYNDROMES OF HUMANS......Page 560
REFERENCES......Page 563
19.1 INTRODUCTION......Page 569
19.2 FUNDAMENTAL ASPECTS OF CLINICAL PHARMACOLOGY......Page 570
19.3 CLASSICAL GENETICS AND PHARMACOGENETICS: 1900 TO APPROXIMATELY 1990......Page 572
19.4 ETHNIC DIFFERENCES IN GENE–DRUG INTERACTIONS......Page 577
19.5 PHARMACOGENOMICS......Page 578
REFERENCES......Page 588
FURTHER READING......Page 594
General Principles......Page 596
20.1 BACKGROUND......Page 598
20.2 THE PROCESS OF GENETIC EVALUATION FOR COMMON DISEASES......Page 599
20.3 INTEGRATING GENETIC INFORMATION INTO ROUTINE CLINICAL PRACTICE......Page 606
REFERENCES......Page 607
21.1 WHAT IS GENETIC COUNSELING?......Page 611
21.2 PROCESS OF GENETIC COUNSELING......Page 615
21.3 ADULT-ONSET DISORDERS......Page 634
21.4 GENETIC RISK ASSESSMENT AND CALCULATION IN THE CLINICAL SETTING......Page 639
REFERENCES......Page 647
FURTHER READING......Page 650
22.2 MILESTONES IN HUMAN CYTOGENETICS......Page 651
22.5 CHROMOSOME BANDING......Page 654
22.6 THE NORMAL HUMAN KARYOTYPE......Page 655
22.7 CHROMOSOME ABNORMALITIES......Page 656
22.8 IN SITU HYBRIDIZATION......Page 657
REFERENCES......Page 665
FURTHER READING......Page 667
23.2 INDICATIONS FOR MOLECULAR GENETIC TESTING......Page 669
23.3 TECHNICAL APPROACHES TO MOLECULAR GENETIC TESTING......Page 671
23.4 MOLECULAR GENETIC DIAGNOSIS OF PARTICULAR DISEASES......Page 676
23.5 MITOCHONDRIAL DNA DISORDERS......Page 689
23.6 OTHER TARGETS OF MOLECULAR GENETIC SCREENING......Page 690
23.8 QUALITY ASSURANCE, REIMBURSEMENT, AND REGULATORY ISSUES......Page 691
23.9 INTERNET RESOURCES FOR MOLECULAR GENETIC TESTING......Page 692
23.10 SOCIETAL IMPACT OF THE NEW GENETIC TECHNOLOGY......Page 693
REFERENCES......Page 695
24.2 CARRIER SCREENING IN CLINICAL PRACTICE......Page 700
24.3 CARRIER SCREENING IN INDIVIDUALS OF DEFINED SUBPOPULATION GROUPS......Page 701
24.5 METHODS AND TISSUES USED IN CARRIER IDENTIFICATION......Page 703
24.6 PROBLEMS IN HETEROZYGOTE DETECTION......Page 704
24.7 SENSITIVITY AND SPECIFICITY......Page 706
24.10 CONCLUSIONS......Page 707
REFERENCES......Page 708
25.2 NEURAL TUBE DEFECTS......Page 710
25.3 ANEUPLOIDY......Page 714
25.4 SUMMARY......Page 722
REFERENCES......Page 723
26.2 AMNIOCENTESIS......Page 733
26.3 CHORIONIC VILLUS SAMPLING......Page 739
26.4 FETAL BLOOD SAMPLING......Page 744
26.5 FETAL TISSUE SAMPLING......Page 745
26.6 COELOCENTESIS......Page 746
26.9 PREIMPLANTATION GENETIC DIAGNOSIS......Page 747
26.10 ULTRASONOGRAPHY......Page 748
26.11 FETAL CELLS AND FETAL DNA IN MATERNAL BLOOD......Page 751
REFERENCES......Page 752
27.2 HISTORICAL ASPECTS......Page 761
27.3 COMPONENTS OF SCREENING PROGRAMS......Page 762
27.4 POTENTIAL PROBLEMS IN NEWBORN SCREENING......Page 766
27.5 DISORDERS AND CONDITIONS DETECTED BY NEWBORN BLOOD SCREENING......Page 768
27.6 OTHER NEWBORN SCREENING......Page 773
27.7 ISSUES AND CONCERNS IN SCREENING......Page 775
GLOSSARY......Page 776
REFERENCES......Page 777
FURTHER READING......Page 780
28.1 INTRODUCTION......Page 782
28.2 ERT FOR LYSOSOMAL STORAGE DISEASES......Page 784
28.3 SUBSTRATE REDUCTION THERAPY......Page 794
28.4 PHARMACOLOGIC CHAPERONE THERAPY......Page 796
28.5 CONCLUSIONS AND FUTURE DIRECTIONS......Page 803
REFERENCES......Page 804
RELEVANT WEBSITES......Page 809
29.1 GENES AS MEDICINES— THE ORIGINS OF GENE THERAPY......Page 812
29.2 THE BASIC SCIENCE: GENE TRANSFER (TABLES 29-1–29-3)......Page 813
29.3 DEVELOPING CELL-TYPE-SPECIFIC AND REGULATABLE GENE DELIVERY VECTORS......Page 823
29.4 THE CLINICAL SCIENCE: TOWARD GENE THERAPY OF HUMAN DISEASE......Page 826
29.5 CODA......Page 835
REFERENCES......Page 836
30.1 INTRODUCTION......Page 844
30.3 GENETIC COUNSELING, TESTING AND SCREENING......Page 845
30.4 GOALS AND OUTCOMES OF GENETIC SERVICES......Page 846
30.5 NONDIRECTIVENESS IN GENETIC COUNSELING......Page 848
30.6 DIAGNOSTIC GENETIC TESTING......Page 849
30.7 PREDICTIVE GENETIC TESTING......Page 852
30.8 CONFIDENTIALITY......Page 853
30.9 GENETIC TESTING IN CHILDHOOD......Page 855
30.10 POPULATION GENETIC SCREENING......Page 857
30.11 NEWBORN SCREENING......Page 858
30.12 ANTENATAL SCREENING......Page 860
30.13 CARRIER SCREENING......Page 865
30.14 OTHER CHALLENGES IN GENETIC COUNSELING......Page 866
30.15 RESEARCH IN HUMAN GENETICS......Page 871
30.16 GENETICS, GENETICIZATION AND SOCIETY......Page 874
30.17 REPRODUCTIVE TECHNOLOGIES AND CLONING: “REPROGENETICS”......Page 876
REFERENCES......Page 878
WEBSITES......Page 882
31.1 INTRODUCTION......Page 884
31.2 GENETIC MALPRACTICE AND THE DUTY TO WARN......Page 885
31.3 GENETIC COUNSELING......Page 886
31.4 ABORTION......Page 887
31.6 SURROGACY......Page 888
31.7 FROZEN EMBRYOS......Page 889
31.8 NEWBORN SCREENING......Page 890
31.10 GENETIC DISCRIMINATION......Page 891
31.12 DIRECT TO CONSUMER GENETIC TESTING......Page 892
31.13 REGULATION OF HUMAN GENETIC RESEARCH......Page 893
31.15 GENES AND PATENTS......Page 894
31.16 THE ORPHAN DRUG ACT......Page 895
REFERENCES......Page 896
RELEVANT WEBSITES......Page 897
Applications to Clinical Problems......Page 899
32.2 THE DIAGNOSIS OF HYPOGONADISM......Page 901
32.6 HYPOGONADOTROPIC HYPOGONADISM......Page 903
32.7 HYPERGONADOTROPIC HYPOGONADISM......Page 911
REFERENCES......Page 919
33.1 MALE INFERTILITY— INTRODUCTION......Page 925
33.2 CHROMOSOME ANOMALIES......Page 926
33.3 GENE DEFECTS INVOLVED IN ENDOCRINE FORMS OF INFERTILITY......Page 930
33.4 MONOGENIC DEFECTS IN POSTTESTICULAR AND PRIMARY TESTICULAR FORMS OF MALE INFERTILITY......Page 935
33.5 SYNDROMIC MONOGENIC DEFECTS......Page 937
REFERENCES......Page 938
34.2 DEFINITION OF TERMS......Page 943
34.3 EARLY PREGNANCY LOSS......Page 944
34.4 LATE PREGNANCY LOSS......Page 954
34.6 CONCLUSIONS......Page 956
REFERENCES......Page 957
RELEVANT WEB SITES......Page 963
35.2 PRENATAL VERSUS POSTNATAL ONSET OF DEVELOPMENTAL PROBLEMS......Page 964
35.3 PRENATAL-ONSET PROBLEMS IN DEVELOPMENT......Page 966
35.5 CONCLUSION......Page 973
REFERENCES......Page 974
36.1 INTRODUCTION......Page 976
36.2 EVALUATING THE PATIENT AND HER EXPOSURE......Page 981
36.3 RECOGNIZED TERATOGENIC EXPOSURES......Page 984
36.5 CONCLUSION......Page 1003
REFERENCES......Page 1004
37.2 GLOBAL DEVELOPMENTAL DELAY......Page 1015
37.3 DEFINITION OF A DIAGNOSIS......Page 1016
37.5 DIAGNOSTIC TESTING OF PATIENTS WITH ID OF UNKNOWN CAUSE......Page 1017
REFERENCES......Page 1026
38.2 PATHOLOGIC SHORT STATURE......Page 1030
38.3 PATHOLOGIC OVERGROWTH......Page 1041
REFERENCES......Page 1049
RELEVANT WEB PAGES......Page 1053
39.1 INTRODUCTION......Page 1055
39.3 GENOME-WIDE ASSOCIATION STUDIES AND HUMAN INFECTION......Page 1056
39.4 CELL SURFACE PROTEINS......Page 1057
39.5 INTRACELLULAR PROTEINS......Page 1064
39.6 EXTRACELLULAR PROTEINS......Page 1066
39.7 CONCLUSION......Page 1070
REFERENCES......Page 1071
40.1 INTRODUCTION......Page 1079
40.2 THE PHYSIOLOGIC FUNCTION OF MHC MOLECULES......Page 1081
40.3 THE STRUCTURE OF HUMAN HISTOCOMPATIBILITY MOLECULES......Page 1082
40.4 THE CHROMOSOMAL ORGANIZATION OF THE HLA COMPLEX......Page 1083
40.5 MINOR HISTOCOMPATIBILITY SYSTEMS......Page 1087
40.6 SEROLOGIC METHODS FOR HLA TYPING......Page 1089
40.7 CELLULAR METHODS FOR HLA TYPING......Page 1091
40.8 MOLECULAR METHODS FOR HLA TYPING......Page 1092
40.9 CLINICAL SIGNIFICANCE OF HLA MOLECULAR TYPING......Page 1097
40.10 GENETICS OF XENOTRANSPLANTATION......Page 1100
40.11 STEM CELLS AND TRANSPLANTATION......Page 1102
40.12 CONCLUSION......Page 1103
REFERENCES......Page 1104
LIST OF USEFUL WEBSITES......Page 1110
41.1 INTRODUCTION......Page 1112
41.2 RESPIRATORY DISTRESS SYNDROME......Page 1113
41.3 BRONCHOPULMONARY DYSPLASIA......Page 1118
41.4 PATENT DUCTUS ARTERIOSUS......Page 1121
41.5 INTRAVENTRICULAR HEMORRHAGE......Page 1122
41.6 RETINOPATHY OF PREMATURITY......Page 1124
41.7 NECROTIZING ENTEROCOLITIS......Page 1126
REFERENCES......Page 1128
42.2 DISORDERS OF NUCLEOTIDE EXCISION REPAIR: XERODERMA PIGMENTOSUM AND COCKAYNE SYNDROME......Page 1134
42.4 DISORDERS OF MISMATCH REPAIR: LYNCH SYNDROME AND TURCOT SYNDROME......Page 1136
42.5 DISORDERS ASSOCIATED WITH DOUBLE STRAND BREAK RECOGNITION AND REPAIR: ATAXIA-TELANGIECTASIA AND RELATED CONDITIONS......Page 1138
42.6 CROSSLINK REPAIR AND HOMOLOGOUS RECOMBINATION DEFECTS: BREAST–OVARIAN CANCER AND FANCONI ANEMIA......Page 1141
42.7 DISORDERS ASSOCIATED WITH RECQ HELICASE DEFICIENCY: BLOOM, WERNER, AND ROTHMUND–THOMSON SYNDROMES......Page 1144
42.8 GENE–ENVIRONMENT INTERACTIONS: GORLIN–GOLTZ SYNDROME......Page 1146
REFERENCES......Page 1147
Applications to Specific Disorders......Page 1150
Chromosomal Disorders......Page 1152
43.2 GENETIC COUNSELING IN THE TRISOMIES......Page 1154
43.3 DOWN SYNDROME (TRISOMY 21)......Page 1155
43.4 TRISOMY 18......Page 1167
43.5 TRISOMY 13......Page 1170
REFERENCES......Page 1173
44.1 INTRODUCTION......Page 1181
44.2 THE EPIDEMIOLOGY OF SEX-CHROMOSOME ABNORMALITIES......Page 1182
44.3 TURNER SYNDROME......Page 1183
44.4 KLINEFELTER SYNDROME......Page 1190
44.5 47,XXX SYNDROME......Page 1195
44.7 SEX CHROMOSOME TETRASOMY AND PENTASOMY (POLYSOMY)......Page 1196
44.8 47,XYY KARYOTYPE......Page 1197
44.9 STRUCTURAL ABNORMALITIES OF THE Y CHROMOSOME......Page 1199
44.10 PRENATAL DIAGNOSIS OF SEX CHROMOSOME ABNORMALITIES......Page 1201
REFERENCES......Page 1203
CROSS REFERENCES......Page 1212
45.1 INTRODUCTION......Page 1213
45.2 TRANSLOCATIONS......Page 1216
45.4 DELETION......Page 1219
45.5 DUPLICATION......Page 1232
REFERENCES......Page 1236
Cardiovascular Disorders......Page 1250
46.2 THE EVALUATION OF THE PATIENT WITH CONGENITAL HEART DEFECT......Page 1252
46.3 SPECIFIC SYNDROMES WITH CONGENITAL HEART DEFECT......Page 1260
46.4 CHROMOSOMAL DISORDERS......Page 1261
46.5 MICRODELETIONS/ MICRODUPLICATION SYNDROMES......Page 1262
46.6 SINGLE-GENE DISORDERS......Page 1264
46.8 CHARGE SYNDROME......Page 1265
46.10 SMITH–LEMLI–OPITZ SYNDROME......Page 1266
46.13 MATERNAL DRUG INGESTION......Page 1268
46.14 FOLIC ACID SUPPLEMENTATION......Page 1269
46.16 EMPIRICAL RISKS FOR OFFSPRING......Page 1270
APPENDIX......Page 1273
REFERENCES......Page 1297
WEBSITES......Page 1301
47.2 HYPERTROPHIC CARDIOMYOPATHY......Page 1303
47.3 DILATED CARDIOMYOPATHY......Page 1319
47.4 ATYPICAL CARDIOMYOPATHIES......Page 1326
REFERENCES......Page 1330
RELEVANT WEBSITES......Page 1339
48.1 HISTORICAL PERSPECTIVES AND INTRODUCTION......Page 1341
48.4 PHENOTYPE AND NATURAL HISTORY OF HPAH AND IPAH......Page 1342
48.5 INHERITANCE AND GENETICS OF PAH IN FAMILIES......Page 1343
TO PAH......Page 1346
48.7 MOLECULAR AND CELLULAR PATHOGENESIS......Page 1348
48.8 DIAGNOSIS......Page 1350
48.9 MANAGEMENT......Page 1351
48.10 COUNSELING......Page 1354
REFERENCES......Page 1355
RELEVANT WEBSITES......Page 1359
49.1 INTRODUCTION......Page 1361
49.2 PHENOTYPE AND NATURAL HISTORY......Page 1362
49.3 ETIOLOGY......Page 1367
49.4 PATHOGENESIS......Page 1368
49.5 DIAGNOSIS......Page 1369
49.6 MANAGEMENT......Page 1370
REFERENCES......Page 1374
50.1 DEVELOPMENT OF THE LYMPHATIC SYSTEM......Page 1379
50.2 DISORDERS OF THE LYMPHATIC SYSTEM......Page 1380
50.3 MENDELIAN DISORDERS AFFECTING BOTH THE LYMPHATIC AND VENOUS SYSTEM......Page 1383
50.4 VARICOSE VEINS......Page 1384
REFERENCES......Page 1385
CROSS REFERENCES......Page 1386
51.3 PRIMARY ABNORMALITIES IN CARDIAC RHYTHM: VENTRICULAR TACHYDYSRHYTHMIAS......Page 1387
51.4 PRIMARY ABNORMALITIES IN CARDIAC RHYTHM: SUPRAVENTRICULAR DYSRHYTHMIAS......Page 1402
51.5 PRIMARY CONDUCTION ABNORMALITIES......Page 1404
51.6 FAMILIAL DYSRHYTHMIAS ASSOCIATED WITH MYOCARDIAL DISEASE......Page 1406
51.7 NEUROLOGIC DISORDERS ASSOCIATED WITH DYSRHYTHMIAS AND CONDUCTION DISEASE......Page 1418
51.8 CONGENITAL HEART DISEASE AND DYSRHYTHMIAS OR CONDUCTION DISEASE......Page 1427
REFERENCES......Page 1429
FURTHER READING......Page 1447
52.1 INTRODUCTION......Page 1449
52.2 MENDELIAN FORMS OF HYPERTENSION......Page 1451
52.3 CANDIDATE GENES......Page 1453
52.4 GENOME-WIDE ASSOCIATION STUDIES......Page 1460
REFERENCES......Page 1462
53.2 CLASSIFICATION......Page 1471
53.3 PATHOLOGIC AND MOLECULAR BASIS......Page 1474
53.4 GENETIC BASIS OF PREECLAMPSIA......Page 1478
53.5 ANIMAL MODELS......Page 1479
REFERENCES......Page 1480
RELEVANT WEB PAGES......Page 1484
54.1 INTRODUCTION......Page 1485
54.2 GENETIC VARIANTS INFLUENCING COMPONENTS OF THE COAGULATION CASCADE......Page 1487
54.3 GENETIC VARIANTS INFLUENCING NATURAL ANTICOAGULANTS......Page 1491
54.5 GENETIC VARIANTS INFLUENCING PLATELET FUNCTION......Page 1493
54.6 GENOME-WIDE ASSOCIATION ANALYSIS FOR THROMBOSIS......Page 1494
54.7 HOW DO WE ACCOUNT FOR THE MISSING HERITABILITY?......Page 1495
REFERENCES......Page 1497
55.1 INTRODUCTION......Page 1505
55.2 CHALLENGES TO GENETIC STUDIES OF CHD......Page 1506
55.3 MOUSE MODELS OF ATHEROSCLEROSIS......Page 1507
55.4 CANDIDATE GENE STUDIES IN HUMANS......Page 1510
55.5 GENOME WIDE ASSOCIATION STUDIES......Page 1515
55.6 GWAS FINDINGS FOR CVD RISK FACTORS......Page 1520
55.7 GENETIC RISK SCORES AND PREDICTION ALGORITHMS FOR PERSONALIZED MEDICINE......Page 1524
55.8 SUMMARY AND FUTURE DIRECTIONS......Page 1525
REFERENCES......Page 1526
FURTHER READING......Page 1540
56.2 THE VENOUS SYSTEM......Page 1542
56.3 DISORDERS OF THE VENOUS SYSTEM......Page 1543
56.4 CONCLUSION......Page 1546
REFERENCES......Page 1547
RELEVANT WEBSITES......Page 1549
57.2 CAPILLARY MALFORMATION......Page 1551
57.3 STURGE–WEBER SYNDROME......Page 1552
57.4 CAPILLARY MALFORMATION– ARTERIOVENOUS MALFORMATION......Page 1553
57.5 CEREBRAL CAVERNOUS MALFORMATION......Page 1554
REFERENCES......Page 1555
RELEVANT WEBSITES......Page 1556
Respiratory Disorders......Page 1558
58.1 INCIDENCE OF CYSTIC FIBROSIS......Page 1560
58.2 CLINICAL FEATURES......Page 1562
58.3 GENETICS......Page 1566
58.4 DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS......Page 1581
58.5 MANAGEMENT......Page 1584
REFERENCES......Page 1588
59.1 INTRODUCTION......Page 1614
59.2 THE GENETICS OF ASTHMA AND ALLERGIC DISEASES......Page 1616
REFERENCES......Page 1624
RELEVANT WEB PAGES......Page 1629
60.2 DISEASES WITH AIRFLOW LIMITATION: DEFINITIONS......Page 1631
60.3 PHENOTYPIC EVALUATION IN COPD......Page 1632
60.4 CIGARETTE SMOKING AND COPD......Page 1636
60.5 SEVERE AAT DEFICIENCY......Page 1637
60.6 RISK OF COPD IN Z ALLELE HETEROZYGOTES......Page 1646
60.7 COPD AND COPD-RELATED PHENOTYPES IN OTHER GENETIC SYNDROMES......Page 1647
60.8 RISK TO RELATIVES FOR NON-AAT COPD......Page 1648
60.10 LINKAGE ANALYSIS......Page 1650
60.11 GENETIC ASSOCIATION STUDIES......Page 1651
60.12 ANIMAL MODELS OF COPD......Page 1653
REFERENCES......Page 1654
RELEVANT WEBSITES......Page 1662
61.2 IDIOPATHIC INTERSTITIAL PNEUMONIA AND FAMILIAL INTERSTITIAL PNEUMONIA......Page 1664
61.3 ASSOCIATED POLYMORPHISMS IN OTHER COMMON FORMS OF ILD......Page 1670
61.4 GENETIC SYNDROMES WITH ILD MANIFESTATIONS......Page 1671
REFERENCES......Page 1676
Renal Disorders......Page 1686
62.1 INTRODUCTION......Page 1688
62.2 CLINICAL FEATURES......Page 1689
62.4 ERRORS OF ORGANOGENESIS......Page 1690
62.5 ERRORS OF MIGRATION AND POSITION......Page 1716
62.6 ERRORS RESULTING IN OBSTRUCTION......Page 1719
REFERENCES......Page 1721
FURTHER READING......Page 1724
63.2 AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (MIM 173900)......Page 1726
63.3 AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE (MIM 263200)......Page 1732
63.4 FAMILIAL NEPHRONOPHTHISIS......Page 1735
63.5 MEDULLARY CYSTIC KIDNEY DISEASE......Page 1743
63.7 GENETIC SYNDROMES WITH CYSTIC RENAL DISEASE AS A MAJOR COMPONENT......Page 1745
63.8 MECHANISMS OF CYSTOGENESIS......Page 1747
REFERENCES......Page 1751
RELEVANT WEB PAGES......Page 1757
64.2 GLOMERULAR FILTRATION BARRIER......Page 1759
MUTATIONS......Page 1760
MUTATIONS......Page 1761
MUTATIONS......Page 1762
MUTATIONS......Page 1763
MUTATIONS......Page 1764
MUTATIONS......Page 1765
64.13 DIAGNOSIS OF NS......Page 1766
64.15 CONCLUSIONS......Page 1767
REFERENCES......Page 1768
CROSS REFERENCE......Page 1771
65.2 GENERALIZED DISORDERS OF TUBULAR FUNCTION (FANCONI SYNDROME)......Page 1772
65.3 DISORDERS OF AMINO ACID TRANSPORT......Page 1773
65.4 RENAL TUBULAR ACIDOSIS......Page 1775
REFERENCES......Page 1776
CROSS REFERENCES......Page 1778
66.1 TUMORS OF THE KIDNEY......Page 1780
66.2 BLADDER NEOPLASMS......Page 1787
66.4 TESTICULAR NEOPLASMS......Page 1788
REFERENCES......Page 1790
CROSS REFERENCES......Page 1796
Gastrointestinal Disorders......Page 1797
67.2 EMBRYOLOGICAL BACKGROUND......Page 1799
67.3 CLASSIFICATION OF GASTROINTESTINAL DISORDERS......Page 1800
REFERENCES......Page 1811
RELEVANT WEB PAGES......Page 1814
68.1 INTRODUCTION AND DISEASE DEFINITION......Page 1816
68.2 PHENOTYPIC HETEROGENEITY......Page 1818
68.3 RACIAL AND ETHNIC DIFFERENCES......Page 1820
68.4 FAMILIAL AGGREGATION......Page 1821
68.6 INFERENCES REGARDING MODE OF INHERITANCE......Page 1822
68.7 ASSOCIATION OF IBD WITH RARE GENETIC SYNDROMES......Page 1824
68.8 ASSOCIATIONS WITH OTHER DISEASES......Page 1826
68.9 GENE AND ENVIRONMENTAL INTERACTIONS......Page 1827
68.10 GENE IDENTIFICATION......Page 1830
68.11 CANDIDATE GENE STUDIES......Page 1833
68.12 CLINICAL APPLICATION OF GENETIC INFORMATION......Page 1839
REFERENCES......Page 1840
FURTHER READING......Page 1852
69.2 FORMATION OF BILIRUBIN......Page 1854
69.3 STRUCTURE OF BILIRUBIN......Page 1856
69.5 TOXIC EFFECTS OF BILIRUBIN......Page 1857
69.6 DISPOSITION OF BILIRUBIN......Page 1858
69.7 BILIRUBIN MEASUREMENT......Page 1862
69.9 DISORDERS OF BILIRUBIN METABOLISM......Page 1863
REFERENCES......Page 1876
70.1 INTRODUCTION......Page 1888
70.2 THE GENETICS OF COLORECTAL CANCER......Page 1889
70.3 FAMILIAL COLORECTAL CANCER......Page 1893
70.4 OTHER FAMILIAL GASTROINTESTINAL POLYPOSIS SYNDROMES......Page 1905
70.5 GENETICS OF GASTRIC CANCER......Page 1910
REFERENCES......Page 1911
Hematologic Disorders......Page 1923
71.2 NORMAL HUMAN HEMOGLOBIN......Page 1925
71.3 HEMOGLOBIN BIOSYNTHESIS......Page 1928
71.4 HUMAN HEMOGLOBIN VARIANTS......Page 1931
71.5 SICKLE-CELL ANEMIA AND RELATED DISORDERS......Page 1935
71.7 HEMOGLOBIN VARIANTS WITH ALTERED OXYGEN AFFINITY......Page 1939
71.9 THALASSEMIAS......Page 1941
REFERENCES......Page 1966
72.1 HEMOLYSIS DUE TO HEREDITARY RED BLOOD CELL ENZYME DISORDERS......Page 1969
72.3 HEMOLYSIS DUE TO HEREDITARY RED BLOOD CELL MEMBRANE DISORDERS......Page 1978
72.4 MEGALOBLASTIC ANEMIAS......Page 1984
72.5 DYSERYTHROPOIETIC ANEMIAS......Page 1986
72.6 SIDEROBLASTIC ANEMIAS......Page 1987
72.7 METHEMOGLOBINEMIA......Page 1988
REFERENCES......Page 1989
73.2 THE COAGULATION CASCADE......Page 1994
73.3 INHERITED DISORDERS PREDISPOSING TO THROMBOSIS......Page 2013
REFERENCES......Page 2020
74.3 DETECTION OF FETOMATERNAL HEMORRHAGE......Page 2027
74.4 RH BLOOD GROUP SYSTEM......Page 2028
74.5 ALLOIMMUNE THROMBOCYTOPENIA......Page 2034
74.6 MANAGEMENT OF ALLOIMMUNIZATION......Page 2035
REFERENCES......Page 2037
FURTHER READING......Page 2040
75.2 GENERAL PATTERNS OF CHROMOSOME ABERRATIONS AND GENOMIC ABNORMALITIES IN LEUKEMIA AND LYMPHOMA......Page 2041
75.3 SIGNIFICANCE OF DETECTING ACQUIRED CHROMOSOME AND GENE ABNORMALITIES IN LEUKEMIA AND LYMPHOMA......Page 2042
75.4 APPLICATION OF CYTOGENETIC, FISH, AND MICROARRAY TECHNIQUES IN DIAGNOSIS OF LEUKEMIA AND LYMPHOMA......Page 2043
75.5 MYELOPROLIFERATIVE NEOPLASM......Page 2044
75.6 MYELODYSPLASTIC SYNDROMES......Page 2046
75.7 ACUTE MYELOID LEUKEMIA DE NOVO......Page 2050
75.8 AML AND MDS ASSOCIATED WITH PRIOR CYTOTOXIC TREATMENT......Page 2055
75.9 B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA......Page 2056
75.10 RECURRING CHROMOSOME AND GENOMIC ABNORMALITIES IN T-CELL ALL......Page 2059
75.13 NON-HODGKIN LYMPHOMAS......Page 2061
75.14 MOLECULAR ANALYSIS OF RECURRENT CHROMOSOME ABNORMALITIES......Page 2068
REFERENCES......Page 2070
76.2 THE IMMUNE RESPONSE......Page 2085
76.3 AUTOIMMUNE PATHOLOGY......Page 2086
76.4 AUTOREACTIVE T CELLS AND THE FAILURE OF TOLERANCE......Page 2087
76.5 GENETICS OF AUTOIMMUNE DISEASES......Page 2089
76.7 GENETIC SUSCEPTIBILITY TO AUTOIMMUNE DISEASE......Page 2090
REFERENCES......Page 2096
77.3 PATHOGENIC AUTOANTIBODIES AND IMMUNE COMPLEXES......Page 2101
77.4 THE GENETICS OF HUMAN SLE......Page 2102
77.6 PREGNANCY COUNSELING OF SLE PATIENTS......Page 2112
REFERENCES......Page 2113
FURTHER READING......Page 2121
78.1 INTRODUCTION......Page 2123
78.2 RHEUMATOID ARTHRITIS......Page 2124
78.3 SERONEGATIVE SPONDYLOARTHROPATHIES......Page 2133
78.4 JUVENILE IDIOPATHIC ARTHRITIS......Page 2142
REFERENCES......Page 2145
79.1 INTRODUCTION......Page 2152
79.2 HEREDITARY SYSTEMIC AMYLOIDOSIS......Page 2153
79.3 HEREDITARY LOCALIZED AMYLOIDOSIS......Page 2161
79.4 HEREDITARY NON-AMYLOID PROTEIN DEPOSITION DISEASE......Page 2162
REFERENCES......Page 2163
80.2 SPECIFIC INHERITED IMMUNODEFICIENCY DISORDERS......Page 2170
80.3 PRIMARY B-CELL DEFICIENCIES (HUMORAL IMMUNE DEFECTS)......Page 2179
80.4 IMMUNODEFICIENCIES WITH IMMUNE DYSREGULATION......Page 2182
80.5 IMMUNODEFICIENCY SYNDROMES......Page 2184
REFERENCES......Page 2188
81.3 THE CLASSICAL PATHWAY......Page 2200
81.7 REGULATION OF COMPLEMENT ACTIVATION......Page 2201
81.8 INHERITED COMPLEMENT DEFICIENCIES......Page 2202
81.9 MANAGEMENT OF COMPLEMENT DEFICIENCIES......Page 2206
REFERENCES......Page 2207
FURTHER READING......Page 2211
Endocrinologic Disorders......Page 2213
82.2 HISTORICAL BACKGROUND......Page 2215
82.3 PHAGOCYTE DEVELOPMENT, KINETICS, AND FUNCTIONS......Page 2216
82.4 GRANULOCYTE FUNCTION DISORDERS......Page 2219
82.5 MONOCYTES/MACROPHAGES FUNCTION DISORDERS......Page 2229
CROSS REFERENCES......Page 2232
REFERENCES......Page 2233
83.2 ANTERIOR PITUITARY......Page 2244
83.3 POSTERIOR PITUITARY: GENETIC DISORDERS OF AVP DEFICIENCY......Page 2271
REFERENCES......Page 2275
84.1 INTRODUCTION......Page 2281
84.2 CONGENITAL HYPOTHYROIDISM......Page 2284
84.5 GENETIC BASIS OF AUTOIMMUNE THYROID DISEASE......Page 2292
84.6 GENETIC BASIS OF THYROID CARCINOMA......Page 2293
REFERENCES......Page 2295
85.2 PRIMARY HYPERPARATHYROIDISM......Page 2305
85.3 FAMILIAL HYPOCALCIURIC HYPERCALCEMIA......Page 2307
85.4 NEONATAL SEVERE HYPERPARATHYROIDISM......Page 2308
MUTATIONS IN FAMILIAL HYPOCALCIURIC HYPERCALCEMIA AND NEONATAL SEVERE HYPERPARATHYROIDISM......Page 2309
85.8 MULTIPLE ENDOCRINE NEOPLASIA TYPE 1......Page 2311
85.9 MULTIPLE ENDOCRINE NEOPLASIA TYPE 2......Page 2313
85.11 HYPERPARATHYROIDISM-JAW TUMOR SYNDROME......Page 2314
85.13 DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF HYPERCALCEMIA......Page 2316
85.15 PRIMARY HYPOPARATHYROIDISM......Page 2317
85.16 FAMILIAL ISOLATED HYPOPARATHYROIDISM......Page 2319
85.17 HYPOPARATHYROIDISM WITH MULTIPLE MALFORMATIONS......Page 2320
85.19 AUTOIMMUNE HYPOPARATHYROIDISM: ACQUIRED AND INHERITED DISORDERS......Page 2321
85.20 PSEUDOHYPOPARATHYROIDISM......Page 2322
MUTATIONS......Page 2327
85.25 MANAGEMENT OF HYPOPARATHYROIDISM......Page 2328
REFERENCES......Page 2330
WEBSITES......Page 2338
86.2 DIFFICULTIES IN GENETIC STUDIES OF DIABETES......Page 2339
86.4 GENETIC HETEROGENEITY IN DIABETES......Page 2340
86.5 TYPE 2 DIABETES MELLITUS......Page 2362
86.6 FINAL CONSIDERATIONS AND SPECULATIONS......Page 2377
REFERENCES......Page 2378
RELEVANT WEB PAGES......Page 2395
87.1 CLINICAL ASPECTS: NORMAL AND ABNORMAL ADRENAL FUNCTION......Page 2397
87.2 STEROID 21-HYDROXYLASE DEFICIENCY......Page 2401
87.3 STEROID 11ß-HYDROXYLASE DEFICIENCY......Page 2407
87.4 3ß-HYDROXYSTEROID DEHYDROGENASE DEFICIENCY......Page 2416
87.5 STEROID 17a-HYDROXYLASE/17,20-LYASE DEFICIENCY......Page 2417
87.6 CONGENITAL LIPOID ADRENAL HYPERPLASIA......Page 2418
87.7 TREATMENT......Page 2419
87.8 CONGENITAL ADRENAL HYPERPLASIA: PRENATAL DIAGNOSIS AND TREATMENT......Page 2421
REFERENCES......Page 2423
FURTHER READING......Page 2432
88.2 46,XX DISORDERS OF SEXUAL DEVELOPMENT......Page 2434
REFERENCES......Page 2467
FURTHER READING......Page 2478
89.2 DISCOVERY OF BRCA1......Page 2479
89.3 DISCOVERY OF BRCA2......Page 2481
89.4 PATHOLOGY OF FAMILIAL BREAST CANCERS......Page 2482
89.5 BRCA1 AND BRCA2 MUTATION ANALYSIS......Page 2483
89.6 RARE FAMILIAL SYNDROMES ASSOCIATED WITH INCREASED RISK FOR BREAST OR OVARIAN CANCER......Page 2486
89.7 LOW-PENETRANCE BREAST CANCER GENES......Page 2489
89.8 ASSOCIATION STUDIES AND GENOMICS OF BREAST CANCER......Page 2490
89.9 HEREDITARY NONPOLYPOSIS COLORECTAL CANCER SYNDROME (OR LYNCH SYNDROME)......Page 2491
89.10 ENDOMETRIAL CANCER......Page 2492
89.11 FAMILIAL OVARIAN CANCER......Page 2493
89.13 IMPLICATIONS OF FAMILIAL BREAST AND OVARIAN CANCERS FOR CLINICAL PRACTICE......Page 2494
89.14 IMPACT OF DEFINITIVE GENETIC DIAGNOSIS ON CLINICAL PRACTICE......Page 2498
REFERENCES......Page 2499
Metabolic Disorders......Page 2510
90.1 OVERVIEW......Page 2512
90.2 GENETIC ARCHITECTURE OF OBESITY......Page 2517
90.3 MENDELIAN DISORDERS ASSOCIATED WITH INCREASED BMI IN HUMANS......Page 2529
REFERENCES......Page 2534
91.2 MECHANISMS OF INSULIN RESISTANCE AND ITS COMPLICATIONS IN LIPODYSTROPHIES......Page 2549
91.3 GENETIC LIPODYSTROPHIES......Page 2550
91.5 TREATMENT OPTIONS......Page 2559
REFERENCES......Page 2560
92.1 DISORDERS OF PHENYLALANINE METABOLISM......Page 2565
92.2 DISORDERS OF TYROSINE METABOLISM......Page 2570
92.3 DISORDERS OF GLYCINE METABOLISM......Page 2574
92.4 DISORDERS OF SULFURCONTAINING AMINO ACIDS......Page 2576
92.5 DISORDERS OF THE BCAAS......Page 2582
92.6 DISORDERS OF PROLINE AND HYDROXYPROLINE......Page 2585
92.7 DISORDERS OF THE UREA CYCLE AND ORNITHINE......Page 2587
92.8 DISORDERS OF SERINE METABOLISM......Page 2596
REFERENCES......Page 2597
FURTHER READING......Page 2605
93.2 DISACCHARIDASE DEFICIENCIES......Page 2607
93.3 GLUCOSE–GALACTOSE MALABSORPTION......Page 2608
93.4 DISORDERS OF GALACTOSE METABOLISM......Page 2609
93.5 DISORDERS OF FRUCTOSE METABOLISM......Page 2612
93.6 DISORDERS OF PENTOSE METABOLISM......Page 2614
93.7 GLYCOGEN STORAGE DISEASES......Page 2615
93.8 GSDS PRIMARILY INVOLVING THE LIVER......Page 2617
93.9 OTHER LIVER GLYCOGENOSES......Page 2623
93.10 GSD PRIMARILY INVOLVING MUSCLE......Page 2624
93.11 GSD PRIMARILY WITH CARDIAC INVOLVEMENT......Page 2628
93.12 GLUCONEOGENIC DISORDERS ASSOCIATED WITH LACTIC ACIDOSIS......Page 2629
REFERENCES......Page 2632
94.2 CONGENITAL DISORDERS OF PROTEIN N-GLYCOSYLATION......Page 2643
94.3 CONGENITAL DISORDERS OF PROTEIN O-GLYCOSYLATION......Page 2646
94.4 CONGENITAL DISORDERS OF PROTEIN NAND O-GLYCOSYLATION......Page 2647
FURTHER READING......Page 2649
95.1 INTRODUCTION......Page 2651
95.2 PURINE METABOLISM......Page 2652
95.3 PYRIMIDINE METABOLISM......Page 2668
REFERENCES......Page 2676
FURTHER READING......Page 2686
96.2 PLASMA LIPIDS, LIPOPROTEINS AND APOLIPOPROTEINS......Page 2689
96.3 LIPOPROTEIN METABOLISM......Page 2691
96.4 MONOGENIC DISORDERS OF LIPOPROTEIN METABOLISM......Page 2693
96.5 DISORDERS WITH PRIMARILY ELEVATED LDL CHOLESTEROL......Page 2696
96.6 DISORDERS WITH PRIMARILY DEPRESSED LDL CHOLESTEROL......Page 2701
96.7 DISORDERS WITH PRIMARILY ELEVATED HDL CHOLESTEROL......Page 2703
96.8 DISORDERS WITH PRIMARILY DEPRESSED HDL CHOLESTEROL......Page 2704
96.9 DISORDERS WITH PRIMARILY ELEVATED TRIGLYCERIDES......Page 2705
96.10 DISORDERS WITH MULTIPLE LIPOPROTEIN DISTURBANCES......Page 2706
96.11 OTHER DYSLIPOPROTEINEMIAS......Page 2708
96.12 GENERAL PRINICIPLES IN THE MANAGEMENT OF DYSLIPIDEMIA......Page 2709
96.13 CONCLUSION......Page 2713
REFERENCES......Page 2714
RELEVANT WEB PAGES......Page 2720
97.1 ORGANIC ACIDEMIAS......Page 2722
97.2 OTHER ORGANIC ACIDEMIAS......Page 2731
97.3 DISORDERS OF FATTY ACID OXIDATION: INTRODUCTION......Page 2738
REFERENCES......Page 2746
RELEVANT WEB PAGES......Page 2754
98.2 NORMAL PHYSIOLOGY OF CALCIFEROLS......Page 2755
98.3 5,6-CIS-TRANS-ISOMERIZATION......Page 2757
98.4 GENERAL FEATURES OF CALCIFEROL DEFICIENCY......Page 2761
HYDROXYLASE DEFICIENCY......Page 2763
98.6 HEREDITARY VITAMIN D-DEPENDENT RICKETS TYPE 2 (VDDR-2)......Page 2765
98.7 STATES RESEMBLING HEREDITARY GENERALIZED RESISTANCE TO 1,25(OH)......Page 2769
98.8 OTHER HEREDITARY DEFECTS IN CALCIFEROL METABOLISM OR ACTION......Page 2770
REFERENCES......Page 2772
FURTHER READING......Page 2781
99.2 THE HEME BIOSYNTHETIC PATHWAY......Page 2783
99.3 REGULATION OF HEME BIOSYNTHESIS......Page 2789
99.4 CLASSIFICATION AND DIAGNOSIS OF THE PORPHYRIAS......Page 2790
FURTHER READING......Page 2808
RELEVANT WEB PAGES......Page 2813
100.1 INTRODUCTION......Page 2815
100.2 MENKES DISEASE......Page 2818
100.3 WILSON DISEASE......Page 2825
REFERENCES......Page 2830
101.2 IRON BALANCE AND THE IRON CYCLE......Page 2836
101.3 SYNDROMES OF IRON OVERLOAD......Page 2841
101.4 OTHER DISORDERS RESULTING IN DERANGEMENTS OF IRON HANDLING......Page 2857
REFERENCES......Page 2860
102.1 GENERAL ASPECTS......Page 2877
102.2 MUCOPOLYSACCHARIDOSIS I (IH HURLER, IS SCHEIE AND IH/S HURLER– SCHEIE DISEASE)......Page 2881
102.3 MUCOPOLYSACCHARIDOSIS II (HUNTER SYNDROME)......Page 2889
102.4 MUCOPOLYSACCHARIDOSIS IIIA (SANFILIPPO SYNDROME, MPS IIIA)......Page 2894
102.6 MUCOPOLYSACCHARIDOSIS IIIC (SANFILIPPO SYNDROME, MPS IIIC)......Page 2897
102.7 MUCOPOLYSACCHARIDOSIS IIID (SANFILIPPO SYNDROME, MPS IIID)......Page 2898
102.8 MUCOPOLYSACCHARIDOSIS IVA AND IVB (MORQUIO SYNDROME, MPS IVA, MPS IVB)......Page 2899
102.10 MUCOPOLYSACCHARIDOSIS VI (MAROTEAUX–LAMY SYNDROME, MPS VI)......Page 2903
102.13 MUCOPOLYSACCHARIDOSIS IX (NATOWICZ SYNDROME, MPS IX)......Page 2907
REFERENCES......Page 2908
FURTHER READING......Page 2916
103.1 OLIGOSACCHARIDOSES......Page 2917
103.2 DISORDERS ALLIED TO OLIGOSACCHARIDOSES......Page 2944
REFERENCES......Page 2957
RELEVANT WEBPAGES......Page 2967
104.1 INTRODUCTION......Page 2968
GALACTOSIDOSIS)......Page 2969
104.3 GM2-GANGLIOSIDOSIS......Page 2973
104.6 NIEMANN–PICK DISEASE, TYPES A AND B......Page 2980
104.7 NIEMANN–PICK DISEASE, TYPES C AND D......Page 2985
104.8 FARBER’S DISEASE......Page 2990
104.9 ACID LIPASE DEFICIENCY (WOLMAN DISEASE AND CHOLESTERYL ESTER STORAGE DISEASE)......Page 2992
104.10 GAUCHER DISEASE......Page 2995
104.11 GALACTOSYLCERAMIDE LIPIDOSIS, GLOBOID CELL LEUKODYSTROPHY, OR KRABBE DISEASE......Page 3002
104.12 METACHROMATIC LEUKODYSTROPHY......Page 3010
104.13 FABRY DISEASE......Page 3016
104.14 NEURONAL CEROID LIPOFUSCINOSIS OR BATTEN DISEASE......Page 3020
104.15 KUFS DISEASE OR ADULT NCL......Page 3029
104.16 CONGENITAL NCL/CNCL-CLN10/ CATHEPSIN D OR CTSD DEFICIENCY......Page 3030
REFERENCES......Page 3031
105.1 INTRODUCTION......Page 3053
105.2 PHYSIOLOGICAL ROLE OF PEROXISOMES......Page 3054
105.3 ADDITIONAL PEROXISOMAL FUNCTIONS......Page 3059
105.4 BIOGENESIS OF PEROXISOMES......Page 3060
105.5 SINGLE PEROXISOMAL ENZYME DEFICIENCIES......Page 3064
105.6 RARE PEROXISOMAL DISORDERS......Page 3070
REFERENCE......Page 3071
Mental and Behavioral Disorders......Page 3075
106.1 THE NATURE OF PERSONALITY......Page 3077
106.2 TWIN AND ADOPTION STUDIES......Page 3078
106.3 THE SEARCH FOR GENES THAT INFLUENCE PERSONALITY......Page 3080
106.4 STRATEGIES TO INCREASE THE SENSITIVITY OF GENETIC STUDIES OF PERSONALITY......Page 3083
REFERENCES......Page 3084
FURTHER READING......Page 3087
107.2 FRAGILE X SYNDROME......Page 3089
107.3 OTHER FORMS OF XLID......Page 3100
REFERENCES......Page 3108
RELEVANT WEBPAGES......Page 3114
108.2 DEFINITION......Page 3116
108.3 PRIMARY COGNITIVE DEFICIT OF SPECIFIC READING DISABILITY......Page 3119
108.4 INHERITANCE......Page 3120
108.5 COMORBIDITY......Page 3126
108.6 RECURRENCE RISKS......Page 3127
108.8 TREATMENT......Page 3128
REFERENCES......Page 3130
109.1 BEHAVIORAL GENETICS......Page 3138
109.2 MOLECULAR GENETICS......Page 3139
109.3 CONCLUSIONS......Page 3142
REFERENCES......Page 3143
RELEVANT WEB PAGES......Page 3145
110.2 DIAGNOSIS AND CLINICAL WORK UP......Page 3146
110.4 ETIOLOGY: GENES AND THE ENVIRONMENT......Page 3147
110.5 PATHOPHYSIOLOGY......Page 3148
110.7 LINKAGE AND ENDOPHENOTYPES......Page 3149
110.9 CANDIDATE GENES......Page 3150
110.10 VARIABLE EXPRESSIVITY AND VARIABLE PENETRANCE—PSYCHIATRIC COMORBIDITY AND DISEASE BOUNDARY CONFUSION......Page 3151
REFERENCES......Page 3153
111.1 BACKGROUND AND HISTORY......Page 3159
111.2 GENETICS OF EOAD......Page 3161
111.3 GENETICS OF LOAD......Page 3163
REFERENCES......Page 3169
FURTHER READING......Page 3176
112.1 INTRODUCTION......Page 3179
112.2 HISTORY AND DEFINITIONS OF THE DISORDERS......Page 3180
112.3 BIOLOGY OF THE DISORDERS......Page 3181
112.4 EVIDENCE SUPPORTING A GENETIC COMPONENT......Page 3184
CROSS REFERENCES......Page 3187
REFERENCES......Page 3188
FURTHER READING AND OTHER SECTIONS REFER TO PPMG ARTICLE TEMPLATE DOC......Page 3194
113.1 INTRODUCTION......Page 3195
113.2 GENETIC ASPECTS OF ADDICTION......Page 3198
113.3 GENE IDENTIFICATION......Page 3208
113.4 TREATMENT OF ADDICTIONS......Page 3216
REFERENCES......Page 3217
Neurologic Disorders......Page 3224
114.1 EMBRYOLOGY......Page 3226
114.3 PREVALENCE......Page 3227
114.4 RISK FACTORS......Page 3228
114.6 PREVENTION......Page 3235
114.7 GENETIC COUNSELING......Page 3236
REFERENCES......Page 3237
FURTHER READING......Page 3245
115.1 INTRODUCTION......Page 3247
115.2 MALFORMATIONS DUE TO ABNORMAL NEURONAL AND GLIAL PROLIFERATION OR APOPTOSIS......Page 3248
115.3 MALFORMATIONS DUE TO ABNORMAL NEURONAL MIGRATION......Page 3252
115.4 MALFORMATIONS DUE TO ABNORMAL CORTICAL ORGANIZATION......Page 3257
115.5 MALFORMATIONS OF CORTICAL DEVELOPMENT, NOT OTHERWISE CLASSIFIED......Page 3259
REFERENCES......Page 3260
LIST OF RELEVANT WEB PAGES......Page 3271
ABBREVIATIONS......Page 3273
116.4 EEG IN EPILEPSY......Page 3274
116.5 SEIZURE TYPES, EPILEPSY SYNDROMES......Page 3275
116.6 GENETIC STUDIES IN HUMAN EPILEPSY......Page 3276
116.7 MECHANISTIC DIVERSITY IN GENETIC EPILEPSY......Page 3279
116.8 SELECTED GENETIC EPILEPSY SYNDROMES......Page 3284
116.9 CLINICAL AND LABORATORY EVALUATION......Page 3296
116.11 PHARMACOGENOMICS ISSUES IN EPILEPSY......Page 3298
116.12 EPILEPSY AND PREGNANCY......Page 3300
CROSS REFERENCES......Page 3301
REFERENCES......Page 3302
RELEVANT WEBPAGES......Page 3312
117.2 DISEASES WITH PARKINSONISM......Page 3313
117.3 PARKINSON DISEASE......Page 3314
117.4 PARKINSON PLUS SYNDROMES......Page 3322
117.5 GENERAL CLINICAL FEATURES OF THE DYSTONIAS......Page 3323
117.7 CHOREIC DISORDERS......Page 3328
117.8 DIFFERENTIAL DIAGNOSIS: OTHER CHOREIC DISORDERS......Page 3334
117.9 CLINICAL FEATURES......Page 3337
REFERENCES......Page 3339
FURTHER READING......Page 3350
118.2 INTERMITTENT ATAXIAS......Page 3352
118.3 PROGRESSIVE ATAXIAS FROM METABOLIC INSUFFICIENCY......Page 3354
118.4 PROGRESSIVE ATAXIAS THAT ARE NOT BECAUSE OF METABOLIC DEFECTS......Page 3355
118.5 PROGRESSIVE ATAXIAS ASSOCIATED WITH DEFECTIVE DNA REPAIR MECHANISMS......Page 3357
118.6 OTHER RECESSIVE PROGRESSIVE ATAXIAS......Page 3360
118.7 THE AUTOSOMAL-DOMINANT HEREDITARY ATAXIAS......Page 3361
118.8 EPISODIC ATAXIAS......Page 3372
118.11 CONCLUSIONS......Page 3373
REFERENCES......Page 3374
LIST OF RELEVANT WEB PAGES......Page 3382
119.1 INTRODUCTION......Page 3384
119.2 MATERNAL (MITOCHONDRIAL GENOME) INHERITANCE......Page 3404
119.3 ASSOCIATION OF HSP GENE MUTATIONS WITH SYNDROMES OTHER THAN SPASTIC PARAPARESIS......Page 3406
119.4 AUTOSOMAL DOMINANT HSP......Page 3413
119.5 AUTOSOMAL RECESSIVE HSP GENES......Page 3416
119.7 EMERGING CONCEPTS OF HSP PATHOGENESIS......Page 3419
119.8 ANIMAL MODELS OF HSP......Page 3420
119.9 CONCLUSIONS......Page 3422
REFERENCES......Page 3423
120.2 FAMILIAL DYSAUTONOMIA......Page 3438
120.3 CONGENITAL SENSORY NEUROPATHY WITH ANHIDROSIS (HSAN TYPE IV)......Page 3443
REFERENCES......Page 3448
121.2 THE NEUROFIBROMATOSES......Page 3451
REFERENCES......Page 3479
122.1 INTRODUCTION......Page 3496
122.3 PRACTICAL APPLICATIONS OF GENETIC STUDIES......Page 3498
REFERENCES......Page 3501
123.1 INTRODUCTION......Page 3504
123.2 STROKE PHENOTYPES......Page 3505
123.4 SINGLE-GENE DISORDERS CAUSING STROKE......Page 3506
PROTHROMBIN)......Page 3518
REFERENCES......Page 3519
124.3 CLASSIFICATION......Page 3524
124.4 INHERITED TUMOR SYNDROMES PREDISPOSING TO CENTRAL NERVOUS SYSTEM TUMORS......Page 3525
124.6 GLIAL TUMORS......Page 3527
124.7 PRIMITIVE NEUROECTODERMAL TUMOR AND MEDULLOBLASTOMA......Page 3535
124.8 SCHWANNOMA (NEURILEMMOMA, NEURINOMA)......Page 3536
124.9 MENINGIOMA......Page 3537
REFERENCES......Page 3538
RELEVANT WEBPAGES......Page 3543
FURTHER READING......Page 3544
Neuromuscular Disorders......Page 3546
GLOSSARY......Page 3548
125.2 DYSTROPHINOPATHIES......Page 3549
125.3 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY......Page 3561
125.4 EMERY–DREIFUSS MUSCULAR DYSTROPHIES AND OTHER CONTRACTURAL PHENOTYPES......Page 3563
125.5 LIMB-GIRDLE MUSCULAR DYSTROPHIES......Page 3569
125.6 MYOFIBRILLAR MYOPATHIES AND OTHER DISTAL PHENOTYPES......Page 3578
125.7 CONGENITAL MUSCULAR DYSTROPHIES......Page 3581
REFERENCES......Page 3593
FURTHER READING......Page 3604
126.2 HEREDITARY MOTOR AND SENSORY NEUROPATHIES......Page 3606
126.3 DISEASES PHENOTYPES......Page 3607
126.6 GENETICS......Page 3609
126.7 CHARCOT–MARIE–TOOTH “DISEASE GENES” REVEAL A CELLULAR AND MYELIN DEVELOPMENT/ MAINTENANCE NETWORK......Page 3616
126.8 GENETIC COUNSELING......Page 3620
REFERENCES......Page 3621
127.2 DIAGNOSIS......Page 3630
127.3 MANAGEMENT......Page 3636
127.4 GENETIC COUNSELING......Page 3637
127.5 NEMALINE (ROD) MYOPATHY......Page 3638
127.6 MYOTUBULAR (CENTRONUCLEAR) MYOPATHIES......Page 3642
127.7 THE “CORE MYOPATHIES”: CCD AND MMD......Page 3645
127.8 CONGENITAL FIBER TYPE DISPROPORTION......Page 3655
127.10 MYOFIBRILLAR MYOPATHIES......Page 3657
REFERENCES......Page 3659
128.2 PROXIMAL SPINAL MUSCULAR ATROPHY......Page 3681
128.3 NONPROXIMAL SPINAL MUSCULAR ATROPHY......Page 3693
128.4 MANAGEMENT......Page 3697
REFERENCES......Page 3698
129.3 HEREDITARY CHANNELOPATHIES AFFECTING THE END PLATE......Page 3704
129.4 HEREDITARY CHANNELOPATHIES AFFECTING THE PLASMALEMMA......Page 3707
129.5 HEREDITARY CHANNELOPATHIES OF EXCITATION–CONTRACTION COUPLING......Page 3713
129.6 CRITICAL POINTS IN FUNCTIONAL AND GENETIC STUDIES......Page 3715
REFERENCES......Page 3716
RELEVANT WEB PAGES......Page 3719
130.2 CLINICAL FEATURES......Page 3721
130.3 DIAGNOSTIC INVESTIGATIONS OF MYOTONIC DYSTROPHY TYPES 1 AND 2......Page 3728
130.4 GENETICS......Page 3729
130.5 MOLECULAR AND CELL BIOLOGY......Page 3735
130.6 GENETIC COUNSELING AND RISK ESTIMATION......Page 3739
130.7 MANAGEMENT......Page 3741
REFERENCES......Page 3742
RELEVANT WEB PAGES......Page 3749
131.3 DIAGNOSTIC METHODS......Page 3751
131.4 ACETYLCHOLINE RECEPTOR......Page 3752
131.5 CONGENITAL MYASTHENIC SYNDROMES......Page 3753
131.6 ACQUIRED AUTOIMMUNE MYASTHENIA GRAVIS......Page 3758
131.7 IMMUNOGENETIC ASSOCIATIONS......Page 3760
131.9 LAMBERT–EATON MYASTHENIC SYNDROME......Page 3761
REFERENCES......Page 3762
FURTHER READING......Page 3765
132.2 HISTORY......Page 3768
132.4 CLINICAL FEATURES......Page 3769
132.7 GENETICS OF FAMILIAL AMYOTROPHIC LATERAL SCLEROSIS......Page 3770
132.8 GENETICS OF SPORADIC AMYOTROPHIC LATERAL SCLEROSIS......Page 3780
REFERENCES......Page 3783
Ophthalmologic Disorders......Page 3790
133.1 INTRODUCTION......Page 3792
133.3 MOLECULAR BIOLOGY OF THE PHOTOPIGMENTS......Page 3793
133.5 GENES ENCODING THE PHOTOPIGMENTS......Page 3794
133.6 COLOR VISION TESTS......Page 3795
133.8 THE MOLECULAR BASIS OF COLOR VISION DEFECTS......Page 3797
133.9 THE GENETICS OF RED–GREEN COLOR VISION IN WOMEN......Page 3802
133.11 THE ACHROMATOPSIAS......Page 3803
REFERENCES......Page 3805
FURTHER READING......Page 3807
134.2 “PRIMARY” OPTIC ATROPHIES......Page 3809
134.3 COMPLEX OPTIC ATROPHIES......Page 3817
REFERENCES......Page 3820
135.2 CLINICAL FEATURES OF HERITABLE FORMS OF GLAUCOMA......Page 3827
135.3 IDENTIFICATION OF GLAUCOMA GENES USING LINKAGE ANALYSIS......Page 3833
135.5 IDENTIFICATION OF GLAUCOMA GENES USING GENOMIC APPROACHES......Page 3835
CROSS REFERENCES......Page 3836
REFERENCES......Page 3837
FURTHER READING......Page 3841
136.2 DYSTROPHIES......Page 3842
136.3 DEFECTS ASSOCIATED WITH SYSTEMIC DISEASE......Page 3858
REFERENCES......Page 3861
137.2 NONCATARACTOUS ANOMALIES......Page 3871
137.3 CATARACTS......Page 3876
137.4 THERAPY......Page 3890
REFERENCES......Page 3891
LIST OF RELEVANT WEB PAGES......Page 3895
138.1 INTRODUCTION......Page 3896
138.2 INHERITANCE PATTERNS AND MOLECULAR GENETICS......Page 3897
138.3 PIGMENTARY RETINOPATHIES/ RETINITIS PIGMENTOSA......Page 3901
138.4 LEBER’S CONGENITAL AMAUROSIS......Page 3904
138.5 THE PRIMARY CONE DEGENERATIONS......Page 3905
REFERENCES......Page 3912
139.3 CLINICAL BACKGROUND......Page 3914
139.4 ISOLATED STRABISMUS......Page 3915
139.5 SINGLE GENE DEFECT DISORDERS......Page 3918
139.7 STRABISMUS ASSOCIATED WITH MULTISYSTEM DISEASE......Page 3921
REFERENCES......Page 3924
140.1 INTRODUCTION......Page 3933
140.3 THEORIES OF TUMORIGENESIS AND......Page 3935
140.4 THE NATURAL HISTORY OF RETINOBLASTOMA TUMORIGENESIS......Page 3936
CANCER SYNDROME......Page 3937
140.6 NON-HERITABLE (SOMATIC OR POSTZYGOTIC) RETINOBLASTOMA......Page 3943
140.7 FEATURES OF RETINOBLASTOMA COMMON TO HERITABLE AND NONHERITABLE CASES......Page 3944
140.8 CLINICAL GENETICS AND GENETIC COUNSELING......Page 3949
140.9 APPROACHES TO PRENATAL ASSESSMENT AND DIAGNOSIS......Page 3953
CROSS REFERENCES......Page 3954
REFERENCES......Page 3955
FURTHER READING......Page 3958
141.1 INTRODUCTION......Page 3960
141.2 ANOPHTHALMIA, MICROPHTHALMIA, AND UVEAL COLOBOMA......Page 3961
141.3 GENES AND SYNDROMES ASSOCIATED WITH ANOPHTHALMIA, MICROPHTHALMIA, AND/OR UVEAL COLOBOMA......Page 3964
141.4 A CLINICAL APPROACH TO THE PATIENT WITH AMC......Page 3968
141.5 PERSISTENCE OF THE FETAL VASCULATURE/PERSISTENT HYPERPLASTIC PRIMARY VITREOUS......Page 3969
REFERENCES......Page 3970
RELEVANT WEBSITES......Page 3974
Deafness......Page 3975
142.1 INTRODUCTION......Page 3977
142.3 PREVALENCE AND CLASSIFICATION OF HL......Page 3978
142.4 ACQUIRED HEARING IMPAIRMENT......Page 3979
142.5 TERATOGENIC HEARING IMPAIRMENT......Page 3980
142.6 NONSYNDROMIC HEREDITARY HEARING IMPAIRMENT......Page 3981
142.7 SYNDROMIC HEREDITARY HEARING IMPAIRMENT......Page 3989
142.9 DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS......Page 3997
REFERENCES......Page 4001
FURTHER READING......Page 4014
Craniofacial Disorders......Page 4015
143.4 GENETICS......Page 4017
143.5 CLINICAL EXAM AND PHYSICAL FINDINGS......Page 4019
REFERENCES......Page 4021
144.2 SKULL AND SUTURAL DEVELOPMENT......Page 4025
144.4 CRANIOSYNOSTOSIS SYNDROMES......Page 4026
144.5 GENES RESPONSIBLE FOR CRANIOSYNOSTOSIS......Page 4038
144.6 OTHER SYNDROMES WITH CRANIOSYNOSTOSIS AND THEIR GENES......Page 4047
144.7 NON-SYNDROMIC CRANIOSYNOSTOSES AND THEIR GENES......Page 4048
144.8 EVALUATION OF CRANIOSYNOSTOSIS......Page 4049
REFERENCES......Page 4051
Dermatologic Disorders......Page 4059
145.1 INTRODUCTION......Page 4061
145.2 THE PIGMENTARY SYSTEM......Page 4063
145.3 GENETICS AND DISORDERS OF HUMAN PIGMENTATION......Page 4068
145.4 DISORDERS OF MELANOSOME BIOGENESIS/TRANSPORT— HERMANSKY–PUDLAK SYNDROME, CHÉDIAK–HIGASHI SYNDROME, AND GRISCELLI SYNDROME......Page 4079
145.5 DISORDERS OF MELANOCYTE SURVIVAL—VITILIGO......Page 4083
REFERENCES......Page 4085
146.3 THE MORPHOLOGY OF NORMAL SKIN......Page 4105
146.4 ICHTHYOSIS VULGARIS......Page 4106
146.5 X-LINKED ICHTHYOSIS......Page 4108
146.6 AUTOSOMAL RECESSIVE CONGENITAL ICHTHYOSIS......Page 4109
146.7 EPIDERMOLYTIC HYPERKERATOSIS......Page 4111
146.8 ICHTHYOSIS OF THE NEWBORN......Page 4113
146.9 HYPERKERATOSIS OF THE PALMS AND SOLES......Page 4115
146.10 RARE ICHTHYOSES......Page 4120
146.11 PHENOTYPE BY FUNCTION: ADVANCES IN UNDERSTANDING......Page 4125
REFERENCES......Page 4126
FURTHER READING......Page 4129
147.2 MOLECULAR BASIS OF EPIDERMAL AND DERMO-EPIDERMAL ADHESION......Page 4131
147.3 CLASSIFICATION......Page 4133
147.4 CLINICAL FEATURES......Page 4134
147.5 DIFFERENTIAL DIAGNOSIS......Page 4141
147.6 MOLECULAR GENETICS OF EPIDERMOLYSIS BULLOSA......Page 4143
147.8 REVERTANT MOSAICISM......Page 4146
REFERENCES......Page 4147
FURTHER READING......Page 4150
LIST OF WEBSITES RELAVANT TO EB......Page 4152
148.1 INTRODUCTION......Page 4155
148.2 HYPOHIDROTIC ECTODERMAL DYSPLASIA......Page 4158
148.3 ODONTO–ONYCHO–DERMAL DYSPLASIA (OODD) SYNDROME (MIM 257980)......Page 4162
148.4 P63-RELATED ECTODERMAL DYSPLASIA SYNDROMES......Page 4163
148.5 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME (MIM 604292)......Page 4164
148.6 ANKYLOBLEPHARON, ECTODERMAL DEFECTS, CLEFT LIP/ PALATE (MIM 106260)......Page 4165
148.7 RAPP–HODGKIN SYNDROME (MIM 129400)......Page 4166
148.11 HIDROTIC ECTODERMAL DYSPLASIA (CLOUSTON SYNDROME) (MIM 129500)......Page 4167
148.12 TOOTH AND NAIL SYNDROME (WITKOP SYNDROME)(MIM 189500)......Page 4169
148.13 IKBKG GENE-RELATED DISORDERS......Page 4170
REFERENCES......Page 4176
RELEVANT WEB PAGES......Page 4179
FURTHER READING......Page 4180
149.2 BASAL CELL CARCINOMA......Page 4181
149.3 NEVOID BASAL CELL CARCINOMA SYNDROME (GORLIN–GOLTZ SYNDROME)......Page 4183
149.4 BAZEX–DUPRE–CHRISTOL SYNDROME......Page 4186
149.5 SQUAMOUS CELL CARCINOMA......Page 4187
149.6 XERODERMA PIGMENTOSUM......Page 4188
149.7 MULTIPLE SELF-HEALING EPITHELIOMAS OF FERGUSON SMITH......Page 4190
149.8 EPIDERMODYSPLASIA VERRUCIFORMIS......Page 4191
149.11 MUIR–TORRE SYNDROME......Page 4192
149.12 MELANOMA......Page 4193
REFERENCES......Page 4198
150.2 CLINICAL FEATURES AND SUBTYPES......Page 4205
150.3 PREVALENCE, AGE AT ONSET AND SEX RATIO......Page 4206
150.4 GENETIC EPIDEMIOLOGY......Page 4207
150.5 ENVIRONMENTAL FACTORS......Page 4208
150.7 HISTOPATHOLOGY AND LESIONAL EVOLUTION......Page 4209
150.8 IMMUNOPATHOGENESIS......Page 4210
150.9 PSORIASIS SUSCEPTIBILITY LOCI AND THEIR ROLES IN DISEASE PATHOGENESIS......Page 4211
150.10 MANAGEMENT......Page 4216
REFERENCES......Page 4217
RELEVANT WEBSITE......Page 4225
151.2 HEREDITARY LEIOMYOMATOSIS AND RENAL-CELL CANCER......Page 4227
151.3 BIRT–HOGG–DUBÉ SYNDROME......Page 4231
REFERENCES......Page 4234
RELEVANT WEB PAGES......Page 4238
GLOSSARY......Page 4240
152.2 HF MORPHOGENESIS AND CYCLING......Page 4241
152.3 THE HAIR KERATINS AND THEIR REGULATION......Page 4242
152.5 GENETICS OF HYPOTRICHOSIS AND OTHER STRUCTURAL HAIR ABNORMALITIES......Page 4243
152.7 OTHER DISORDERS ASSOCIATED WITH HAIR PHENOTYPES......Page 4252
152.8 HYPERTRICHOSIS......Page 4253
152.9 GENETICS OF POLYGENIC DISEASES......Page 4256
REFERENCES......Page 4257
Connective Tissue Disorders......Page 4262
Marfan Syndrome and Related Disorders......Page 4264
153.3 FIBRILLINS......Page 4265
153.4 FUNCTIONS OF MICROFIBRILS......Page 4268
153.5 MARFAN SYNDROME (OMIM *154700): THE PROTOTYPE OF DISORDERS OF MICROFIBRILOGENESIS AND THE FIBRILLINS......Page 4269
153.6 DISORDERS RELATED TO MARFAN SYNDROME THROUGH PHENOTYPE, ETIOLOGY OR PATHOGENESIS......Page 4297
REFERENCES......Page 4304
154.2 COLLAGEN GENES AND PROTEINS......Page 4316
154.3 BIOSYNTHESIS OF COLLAGENS......Page 4317
154.4 CLASSICAL EHLERS–DANLOS SYNDROME (TYPES I AND II—GRAVIS AND MITIS)......Page 4318
154.5 HYPERMOBILE TYPE (EDS TYPE III—FAMILIAL HYPERMOBILITY)......Page 4321
154.6 VASCULAR, ECCHYMOTIC TYPE (EDS TYPE IV)......Page 4322
154.7 KYPHYOSCOLIOTIC EHLERS– DANLOS SYNDROME (EDS TYPE VI)......Page 4325
154.8 ARTHROCHALASIS TYPES OF EHLERS–DANLOS SYNDROME (EDS TYPES VIIA AND VIIB)......Page 4327
154.9 DERMATOSPARAXIS (EDS TYPE VIIC)......Page 4328
154.10 OTHER FORMS OF EHLERS– DANLOS SYNDROME......Page 4330
154.11 SUMMARY......Page 4332
REFERENCES......Page 4333
155.1 INTRODUCTION......Page 4339
155.2 BIOLOGY OF ELASTIN......Page 4340
155.3 ELASTIN DEFICIENCY DISORDERS......Page 4345
155.4 ELASTIN ACCUMULATION DISEASES......Page 4351
155.5 DISORDERS OF ELASTIN FIBRILLOGENESIS......Page 4360
REFERENCES......Page 4362
Skeletal Disorders......Page 4369
156.2 OSTEOGENESIS IMPERFECTA......Page 4371
156.3 MANAGEMENT OF OSTEOGENESIS IMPERFECTA......Page 4374
156.4 CLINICAL FEATURES OF THE OI SYNDROMES......Page 4378
156.5 OTHER MANIFESTATIONS OF OSTEOGENESIS IMPERFECTA......Page 4387
156.6 SYNDROMES WITH OSTEOPOROSIS AND EYE DISEASE......Page 4388
156.7 HYPOPHOSPHATASIA......Page 4389
156.8 OTHER BONE FRAGILITY DISORDERS......Page 4390
REFERENCES......Page 4391
157.2 OSTEOPETROSIS GROUP OF DISORDERS......Page 4397
157.4 PYKNODYSOSTOSIS......Page 4401
157.7 OSTEOPATHIA STRIATA......Page 4402
157.8 CRANIOTUBULAR REMODELING DISORDERS......Page 4403
157.9 CRANIOTUBULAR REMODELING DISORDERS RESULTING FROM MUTATIONS IN FILAMIN A......Page 4407
157.10 TUBULAR STENOSIS (KENNY–CAFFEY SYNDROME)......Page 4408
157.12 DISORDERS OF PARATHYROID HORMONE RESISTANCE......Page 4409
157.13 X-LINKED HYPOPHOSPHATEMIC RICKETS......Page 4411
REFERENCES......Page 4413
158.2 CLASSIFICATION AND NOMENCLATURE......Page 4417
158.3 CLINICAL EVALUATION......Page 4438
158.4 RADIOLOGIC EVALUATION......Page 4441
158.5 CHONDRO-OSSEOUS MORPHOLOGY......Page 4442
158.5 BIOCHEMICAL AND MOLECULAR ABNORMALITIES......Page 4444
REFERENCES......Page 4448
FURTHER READING......Page 4450
159.1 INTRODUCTION......Page 4462
159.3 HEREDITARY MULTIPLE EXOSTOSES......Page 4463
159.4 LANGER–GIEDION SYNDROME......Page 4465
159.5 ENCHONDROMATOSIS......Page 4466
159.6 MAFFUCCI SYNDROME......Page 4467
159.8 FIBROUS DYSPLASIA OF BONE......Page 4468
159.9 CHERUBISM......Page 4471
REFERENCES......Page 4472
RELEVANT WEBSITES......Page 4476
160.2 DYSOSTOSES WITH PREDOMINANTLY AXIAL INVOLVEMENT......Page 4477
160.3 PREDOMINANT LIMB INVOLVEMENT......Page 4481
160.4 PREDOMINANT LIMB INVOLVEMENT WITH OTHER ASSOCIATED ABNORMALITIES......Page 4487
REFERENCES......Page 4492
FURTHER READING......Page 4497
161.1 INTRODUCTION......Page 4499
161.2 APPROACH......Page 4500
161.3 DIFFERENTIAL DIAGNOSIS......Page 4506
161.4 FREQUENTLY OBSERVED CONDITIONS......Page 4567
REFERENCES......Page 4572
RELEVANT WEBSITES......Page 4599
162.2 IDIOPATHIC SCOLIOSIS......Page 4600
162.4 CONGENITAL DISLOCATION OF THE HIP......Page 4603
162.5 CLUBFOOT......Page 4605
162.6 JUVENILE OSTEOCHONDROSES......Page 4606
REFERENCES......Page 4607
RELEVANT WEBSITE......Page 4609
163.2 SPONDYLOEPIPHYSEAL DYSPLASIAS......Page 4610
163.3 FAMILIAL OSTEOARTHROPATHY......Page 4611
163.5 MSELENI JOINT DISEASE......Page 4614
ACKNOWLEDGMENTS......Page 4615
REFERENCES......Page 4616
Pathways......Page 4619
164.2 CLINICAL FEATURES OF CdLS......Page 4621
164.4 GENETICS......Page 4624
164.5 OTHER DISORDERS OF COHESIN AND SISTER CHROMATID COHESION......Page 4628
REFERENCES......Page 4630
165.1 CILIA STRUCTURE AND FUNCTION......Page 4635
165.2 CLINICAL ASPECTS OF CILIOPATHIES AND CILIOPATHY-LIKE DISORDERS......Page 4637
165.3 CLINICAL ASPECTS OF CILIOPATHIES......Page 4652
165.4 MOLECULAR AND DEVELOPMENTAL MECHANISMS IN CILIOPATHIES......Page 4658
165.5 DIRECT INTERACTIONS BETWEEN CILIOPATHY PROTEINS AND EVIDENCE FOR COMPLEX INHERITANCE IN A SUBSET OF FAMILIES......Page 4662
REFERENCES......Page 4663
RELEVANT WEBSITE......Page 4670