Genetic Diagnosis of Endocrine Disorders (eBook)

Front Cover 1
Genetic Diagnosis of Endocrine Disorders 4
Copyright Page 5
Contents 6
Contributors 8
Preface 10
SECTION 1 Introduction 12
CHAPTER 1 Mechanisms of Mutation 14
INTRODUCTION 14
POINT MUTATIONS 15
MUTAGENIC AGENTS 15
SPECIFICITY RULES 17
MUTAGENIC POLYMERASES 18
MUTATION MODIFIERS 18
MISMATCH REPAIR 20
MUTATION OUTSIDE THE REPLICATION CYCLE 21
SPONTANEOUS MUTATION AND TUMORIGENESIS 21
THE ROLE OF DNA STRUCTURE 22
References 24
SECTION 2 Pancreas 26
CHAPTER 2 Genetic Testing in Diabetes Mellitus: A Clinical Guide to Monogenic Diabetes 28
INTRODUCTION 28
MONOGENIC FORMS OF DIABETES MELLITUS 31
CONCLUSIONS AND SUMMARY 35
References 35
CHAPTER 3 Obesity 38
INTRODUCTION 38
GENETIC PATHOPHYSIOLOGY 38
DIAGNOSIS, GENETIC TESTING AND INTERPRETATION 44
TREATMENT 45
References 46
CHAPTER 4 Syndromes of Severe Insulin Resistance and/or Lipodystrophy 50
INTRODUCTION 50
GENETIC PATHOPHYSIOLOGY 53
DIAGNOSIS, GENETIC TESTING AND INTERPRETATION 58
TREATMENT 61
References 62
SECTION 3 Pituitary 64
CHAPTER 5 Functioning Pituitary Adenomas 66
INTRODUCTION 66
GENETIC PATHOPHYSIOLOGY OF PITUITARY ADENOMAS 67
GENETIC SCREENING IN FUNCTIONING PITUITARY ADENOMAS 68
MEN1 68
CARNEY COMPLEX (CNC) 70
MULTIPLE ENDOCRINE NEOPLASIA 4 (MEN4) 70
FAMILIAL ISOLATED PITUITARY ADENOMAS (FIPA) 71
References 73
CHAPTER 6 Diabetes Insipidus 78
INTRODUCTION 78
DEFINITION 78
CLINICAL TYPES OF DIABETES INSIPIDUS 78
FAMILIAL TYPES OF DIABETES INSIPIDUS 79
FNDI 79
NDI 80
OTHER GENETIC DEFECTS THAT CAUSE NEPHROGENIC POLYURIA 81
AVAILABLE LABORATORIES AND RESOURCES 83
References 83
CHAPTER 7 States of Pituitary Hypofunction 86
INTRODUCTION 86
GENETIC PATHOPHYSIOLOGY 86
DIAGNOSIS, GENETIC TESTING AND INTERPRETATION 91
TREATMENT 91
References 93
SECTION 4 Thyroid 96
CHAPTER 8 Congenital Defects of Thyroid Hormone Synthesis 98
INTRODUCTION 98
PATHOPHYSIOLOGY AND GENETICS OF SPECIFIC DYSHORMONOGENESIS DEFECTS 98
AVAILABILITY OF GENETIC TESTING 103
CONCLUSION 104
ACKNOWLEDGMENT 104
References 104
CHAPTER 9 Developmental Abnormalities of the Thyroid 108
INTRODUCTION 108
TSH RECEPTOR GENE MUTATIONS (LOSS-OF-FUNCTION) 109
PAX8 GENE MUTATIONS 109
TTF1 GENE MUTATIONS 110
TTF2 (FOXE 1 OR FKHL15) GENE MUTATIONS 110
GLIS3 GENE MUTATIONS 111
NKX2.5 GENE MUTATIONS 112
SYNDROMES ASSOCIATED WITH CH FROM THYROID DYSGENESIS 112
TSH RECEPTOR MUTATIONS (GAIN-OF-FUNCTION) 112
CONCLUSIONS 112
References 112
CHAPTER 10 Syndromes of Reduced Sensitivity to Thyroid Hormone 116
INTRODUCTION 116
OVERVIEW OF DESCRIBED AND PUTATIVE DEFECTS IN SYNDROMES OF REDUCED SENSITIVITY TO THYROID HORMONE 117
RESISTANCE TO THYROID HORMONE (RTH) 118
THYROID HORMONE CELL TRANSPORTER DEFECT (THCTD) 121
THYROID HORMONE METABOLISM DEFECT (THMD) 123
References 124
CHAPTER 11 Molecular Genetics of Thyroid Cancer: Pathogenetic Significance and Clinical Applications 128
INTRODUCTION 128
THE RET ONCOGENE IN MEDULLARY AND PAPILLARY THYROID CANCER 128
ROLE OF RET IN THE MOLECULAR PATHOPHYSIOLOGY OF PTC 137
RET AS A THERAPEUTIC TARGET IN THYROID CARCINOMA 138
BRAF AND ITS ROLE IN CANCER 139
RAS MUTATIONS 141
NTRK1 CHROMOSOMAL REARRANGEMENTS IN THYROID CANCER 141
BIOCHEMISTRY AND BIOLOGICAL PROPERTIES OF THE PI3K/AKT/PTEN PATHWAY 142
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CONCLUDING REMARKS 145
References 146
SECTION 5 Parathyroid and Bone 150
CHAPTER 12 Genetics of Hyperparathyroidism Including Parathyroid Cancer 152
INTRODUCTION 152
HYPERPARATHYROIDISM-JAW TUMOR SYNDROME (HPT-JT), HRPT2 AND PARATHYROID CARCINOMA 152
FAMILIAL HYPOCALCIURIC HYPERCALCEMIA (FHH) AND NEONATAL SEVERE HYPERPARATHYROIDISM (NSHPT) 155
AUTOSOMAL DOMINANT HYPOPARATHYROIDISM 156
FAMILIAL ISOLATED HYPERPARATHYROIDISM 157
SUMMARY 157
References 158
CHAPTER 13 Genetic Diagnosis of Skeletal Dysplasias 160
INTRODUCTION 160
GROWTH PLATE CHONDROCYTE REGULATORY GENES 160
SOX-9 161
FGF-RECEPTOR 162
PTHRP-RECEPTOR 162
RUNX2 163
MATRIX COMPONENTS 163
References 164
CHAPTER 14 Vitamin D Disorders 166
INTRODUCTION 166
CALCIUM, PHOSPHORUS AND VITAMIN D METABOLISM 166
VITAMIN D DEFICIENCY AND RICKETS 168
GENETIC CAUSES OF RICKETS – OSTEOMALACIA: DISORDERS IN VITAMIN D METABOLISM AND RECOGNITION 168
GENETIC CAUSES OF RICKETS: HYPOPHOSPHATEMIC DISORDERS 171
References 173
SECTION 6 Adrenal 174
CHAPTER 15 Congenital Adrenal Hyperplasia 176
INTRODUCTION 176
GENETIC PATHOPHYSIOLOGY 177
DIAGNOSIS GENETIC TESTING AND INTERPRETATION 178
TREATMENT 180
RESOURCES 182
References 182
CHAPTER 16 Genetics of Adrenocortical Tumors (ACT) and Hypersecretory Syndromes 184
INTRODUCTION 184
CONCLUSION 188
ACKNOWLEDGMENTS 189
References 189
CHAPTER 17 Hereditary Pheochromocytoma and Multiple Endocrine Neoplasia Type 2 (MEN2) 192
MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 192
VON HIPPEL–LINDAU SYNDROME (VHL) 194
NEUROFIBROMATOSIS TYPE 1 (NF1) 196
FAMILIAL PARAGANGLIOMA SYNDROMES 196
GENETIC RISK ASSESSMENT IN PATIENTS WITH APPARENTLY SPORADIC PHEOCHROMOCYTOMA 198
SUMMARY 201
References 201
CHAPTER 18 Genetic Conditions Associated with Congenital Adrenocortical Insufficiency or Glucocorticoid and/or Mineralocorticoid Resistance 204
INTRODUCTION 204
GENETICS OF EMBRYOLOGY AND FUNCTION OF THE ADRENAL GLANDS 204
GENETIC DEFECTS CAUSING CAI: AN OVERVIEW AND A COMMENT ON TREATMENT 205
SPECIFIC GENETIC CONDITIONS ASSOCIATED WITH CAI 207
APECED (MEA-1) 210
GENETIC CONDITIONS ASSOCIATED WITH RESISTANCE TO GLUCOCORTICOIDS OR MINERALOCORTICOIDS 210
ACKNOWLEDGMENTS 212
References 212
SECTION 7 Reproductive 216
CHAPTER 19 Genetic Considerations in the Evaluation of Menstrual Cycle Irregularities 218
INTRODUCTION 218
OVARIAN DISORDERS 218
ADRENAL DISORDERS 223
CLINICAL AND LABORATORY EVALUATION 224
CONCLUSION 224
References 224
CHAPTER 20 Genetic Diagnosis of Hypogonadotropic Hypogonadism and Kallmann Syndrome 228
INTRODUCTION 228
DELAYED PUBERTY 228
THE DIAGNOSIS OF HYPOGONADISM 228
THE MOLECULAR BASIS OF IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM/KALLMANN SYNDROME 229
KAL1 GENE MUTATIONS 231
FGFR1 MUTATIONS 231
CHD7 GENE 232
GNRHR GENE MUTATIONS 232
OTHER GENES ASSOCIATED WITH IHH/KS 232
NROB1 GENE MUTATIONS 232
KISS1R GENE MUTATIONS 233
LEP AND LEPR GENE MUTATIONS 233
PUTATIVE IHH/KS GENES 233
NELF GENE 233
PROK2 AND PROKR2 GENES 233
PITUITARY GENE MUTATIONS 233
NEW GENES REPORTED TO CAUSE NORMOSMIC IHH 233
CONCLUSIONS 234
ACKNOWLEDGMENTS 234
References 235
CHAPTER 21 Disorders of Sex Development 238
INTRODUCTION 238
DISORDERS OF SEX DETERMINATION 238
DISORDERS OF SEX DIFFERENTIATION 246
CONCLUSION 251
References 251
CHAPTER 22 Genetic Defects of Androgen Resistance 256
INTRODUCTION 256
GENETIC PATHOPHYSIOLOGY OF ANDROGEN RESISTANCE 256
DIAGNOSIS GENETIC TESTING AND INTERPRETATION 262
MANAGEMENT 262
CONCLUSION 264
AVAILABILITY OF GENETIC TESTING INFORMATION AND SUPPORT GROUPS 264
References 265
SECTION 8 Multisystem Disorders 270
CHAPTER 23 Multiple Endocrine Neoplasia Type 1 (MEN1) 272
INTRODUCTION 272
GENETIC PATHOPHYSIOLOGY OF MEN1 276
MEN1 MUTATION ANALYSIS 277
TREATMENT 279
CONCLUSIONS 279
ACKNOWLEDGMENT 280
References 280
CHAPTER 24 Genetics of Polyglandular Failure 282
INTRODUCTION 282
GENETIC PATHOPHYSIOLOGY 283
DIAGNOSIS, GENETIC TESTING AND INTERPRETATION 285
TREATMENT 288
References 288
SECTION 9 Growth 292
CHAPTER 25 Genetic Diagnosis of Growth Failure 294
INTRODUCTION 294
GENETIC PATHOPHYSIOLOGY 296
DIAGNOSIS: GENETIC TESTING AND INTERPRETATION 299
TREATMENT 300
References 301
SECTION 10 Counseling and Laboratory 302
CHAPTER 26 Genetic Counseling 304
INTRODUCTION 304
HOW COMMON ARE GENETIC CONDITIONS? 304
THE ROLE OF GENETIC COUNSELORS IN THE HEALTH CARE PROVIDER TEAM 305
THE GENETIC COUNSELING PROCESS 307
THE PEDIGREE: MEDICINE AND ART 307
PEDIGREE ANALYSIS AND RISK PERCEPTION 309
SUMMARY 312
References 312
CHAPTER 27 Setting up a Laboratory 314
INTRODUCTION 314
REGULATIONS FOR CLINICAL LABORATORY TESTING 314
HIPAA 315
SPACE 316
THE TESTING PROCESS 316
SAMPLE HANDLING (PRE-ANALYTIC) 317
SPECIMEN HANDLING 317
SPECIMEN PROCESSING 317
ANALYTE QUALITY ASSESSMENT 318
SAMPLE STORAGE 319
ANALYTIC PHASE 319
POST-ANALYTIC PHASE 320
ANALYTICAL TESTING STRATEGIES 320
NOTES ON ANALYTICAL METHODS 322
INSTRUMENTATION 324
SUMMARY 325
References 325
Index 326
A 326
B 327
C 327
D 328
E 328
F 328
G 329
H 329
I 330
J 330
K 330
L 330
M 331
N 331
O 331
P 332
R 333
S 333
T 333
U 334
V 334
W 334
X 334
Y 334
Z 334
Colour Plates 336