Genetic Disorders and the Fetus

1 Genetic Counseling: Prelude to Prenatal Diagnosis.- 1. Introduction.- 2. Guiding Principles in Genetic Counseling.- 2.1. Accurate Diagnosis.- 2.2. Nondirective Counseling.- 2.3. Concern for the Individual.- 2.4. Truth in Counseling.- 2.5. Confidentiality and Trust.- 2.6. Timing of Genetic Counseling.- 2.7. Parental Counseling.- 3. Prerequisites for Genetic Counseling.- 3.1. Knowledge of the Disease.- 3.2. Physician as Counselor.- 3.3. Ability to Communicate.- 3.4. Knowledge of Ancillary Needs.- 3.5. Humanity.- 3.6. Efficacy of Genetic Counseling.- 4. Principles in Practice: Considerations Prior to Amniocentesis and Prenatal Genetic Studies.- 5. Addendum.- 6. References.- 2 Amniocentesis.- 1. Introduction.- 2. Counseling and Consent.- 3. Ultrasound Prior to Amniocentesis.- 4. Amniocentesis Technique.- 5. Timing.- 6. Amniotic Fluid Volume Required.- 7. Risks of Second Trimester Amniocentesis.- 7.1. Fetal Risks.- 7.2. Maternal Risks.- 8. The Newborn Infant and the Child at 1 Year of Age following Amniocentesis.- 9. Addendum.- 10. References.- 3 Amniotic Fluid.- 1. Introduction.- 2. Amniotic Fluid Dynamics.- 2.1. Formation and Circulation.- 2.2. Volume.- 2.3. Origin.- 3. Biochemical and Other Characteristics of Amniotic Fluid.- 3.1. Proteins.- 3.2. Lipids.- 3.3. Enzymes.- 3.4. Disaccharidases.- 3.5. Amino Acids.- 4. Miscellaneous Biochemical Constituents and Other Characteristics of Amniotic Fluid.- 4.1. Creatinine.- 4.2. Blood Group Substances.- 4.3. Antibacterial Activity of Amniotic Fluid.- 5. Addendum.- 6. References.- 4 Amniotic Fluid Cell Culture.- 1. Cell Types.- 2. Cell Viability.- 3. Culture Techniques.- 3.1. Culture Media.- 3.2. Stimulating Cell Growth.- 4. Culture Results.- 5. Problems and Pitfalls.- 5.1. Bloody Samples.- 5.2. Mycoplasma Contamination.- 5.3. Syringe Toxicity.- 5.4. Bacterial or Fungal Contamination.- 5.5. Transport and Storage of Amniotic Fluid Cells.- 6. Karyotyping of Amniotic Fluid Cells without Culturing.- 7. Some Notes on the Establishment of a Prenatal Diagnostic Laboratory.- 8. References.- 5 Prenatal Diagnosis of Chromosomal Disorders.- 1. Introduction.- 2. Frequency of Chromosomal Disorders.- 3. Frequency of Chromosomal Disorders in Fetuses and Live Births.- 4. Worldwide Survey of Prenatal Diagnosis Experience.- 5. Indications for Prenatal Diagnosis of Chromosomal Disorders.- 5.1. Maternal Age.- 5.2. Translocation Carriers.- 5.3. Previous Child with Down Syndrome (Trisomy 21).- 5.4. Advanced Paternal Age.- 5.5. Miscellaneous Indications.- 6. Problems and Pitfalls.- 6.1. Mycoplasma Contamination.- 6.2. Chromosomal Mosaicism.- 6.3. Twins.- 6.4. Polyploidy.- 6.5. Maternal Cell Admixture.- 6.6. Unexpected Abnormal Fetal Karyotype.- 6.7. Chromosomal Polymorphisms.- 6.8. Noncytogenetic Indications for Prenatal Studies.- 6.9. "Unnecessary" Prenatal Studies: Drugs, Chemicals, and Irradiation.- 7. Errors in Prenatal Diagnosis.- 8. Automated Chromosomal Analysis.- 9. Addendum.- 10. References.- 6 Sex Chromosome and X-Linked Disorders.- 1. Introduction.- 2. Prenatal Diagnosis of Sex Chromosome Disorders.- 2.1. Sex Chromosome Disorders in Phenotypic Males.- 2.2. Sex Chromosome Disorders in Phenotypic Females.- 3. Translocations Involving Sex Chromosomes and Autosomes.- 4. Prenatal Diagnosis of X-Linked Disorders.- 5. Fetal Sex Determination.- 5.1. Sex Chromatin Mass (Barr Body).- 5.2. Y-Chromosome Flourescence.- 5.3. Complete Chromosomal Analysis.- 5.4. Amniotic Fluid Testosterone.- 6. Preconception Sex Selection.- 7. Prenatal Diagnosis of Specific X-Linked Disorders.- 7.1. Lesch-Nyhan Syndrome.- 7.2. Fabry Disease.- 7.3. Hunter Syndrome.- 7.4. Glucose-6-phosphate Dehydrogenase Deficiency.- 7.5. Menkes Kinky Hair Disease.- 7.6. X-Linked Ichthyosis.- 8. X-Linked Disorders Potentially Diagnosable in Utero.- 8.1. Adrenoleukodystrophy.- 8.2. The Androgen Resistance Syndromes.- 8.3. Chronic Granulomatous Disease.- 8.4. Combined Immunodeficiency Disease.- 8.5. Duchenne Muscular Dystrophy.- 9. Coagulation Disorders.- 10. Miscellaneous X-Linked Disorders.- 11. Addendum.- 12. References.- 7 Prenatal Diagnosis of Hereditary Biochemical Disorders of Metabolism.- 1. Introduction.- 2. Disorders of Lipid Metabolism.- 2.1. Tay-Sachs Disease (GM2 Gangliosidosis Type I).- 2.2. Sandhoff Disease (GM2 Gangliosidosis Type II).- 2.3. Juvenile GM2 Gangliosidosis (GM2 Gangliosidosis Type III).- 2.4. Juvenile Sandhoff Disease (GM2 Gangliosidosis Type IV).- 2.5. Adult (Chronic) GM2 Gangliosidosis (GM2 Gangliosidosis Type V).- 2.6. Generalized Gangliosidosis (Infantile GM1 Gangliosidosis Type I).- 2.7. Juvenile GM1 Gangliosidosis (Type II).- 2.8. Adult GM1 Gangliosidosis (Type III).- 2.9. Other Disorders with ?-Galactosidase Deficiency.- 2.10. Farber Disease (Ceramidase Deficiency).- 2.11. Gaucher Disease.- 2.12. Globoid Cell Leukodystrophy (Krabbe Disease).- 2.13. Fabry Disease (?-Galactosidase Deficiency).- 2.14. Familial Hyperlipoproteinemias.- 2.15. Familial Hypercholesterolemia.- 2.16. Metachromatic Leukodystrophy (Sulfatide Lipidosis).- 2.17. Multiple Sulfatase Deficiency (Mucosulfatidosis).- 2.18. Niemann-Pick Disease.- 2.19. Phytanic Acid Storage Disease (Refsum Syndrome).- 2.20. Wolman Disease and Cholesteryl Ester Storage Disease (Acid Cholesteryl Ester Hydrolase Deficiency).- 2.21. GM3 Sphingolipidystrophy.- 3. Disorders of Mucopolysaccharide Metabolism.- 3.1. Hurler Syndrome (?-L-Iduronidase Deficiency: Mucopolysaccharidosis IH).- 3.2. Scheie Syndrome (?-L-Iduronidase Deficiency: Mucopolysaccharidosis IS).- 3.3. Hurler-Scheie Compound Disease (?-L-Iduronidase Deficiency: Mucopolysaccharidosis IH/S).- 3.4. Hunter Syndrome (Iduronate Sulfatase Deficiency: Mucopolysaccharidosis II).- 3.5. Sanfilippo Syndrome (Mucopolysaccharidosis III).- 3.6. Morquio Syndrome (Mucopolysaccharidosis IV).- 3.7. Maroteaux-Lamy Syndrome (Mucopolysaccharidosis VI).- 3.8. ?-Glucuronidase Deficiency (Mucopolysaccharidosis VII).- 3.9. Glucosamine-6-sulfate Sulfatase Deficiency (Mucopolysaccharidosis VIII).- 4. Disorders of Carbohydrate Metabolism.- 4.1. Glycogen Storage Diseases.- 4.2. Galactosemia.- 4.3. Galactokinase Deficiency.- 4.4. Uridine Diphosphate Galactose-4-epimerase Deficiency.- 4.5. Mannosidosis.- 4.6. Fucosidosis.- 4.7. Mucolipidoses.- 4.8. Hereditary Hemolytic Anemias.- 5. Amino Acid and Related Disorders of Metabolism.- 5.1. Urea Cycle Disorders.- 5.2. Hyperlysinemia.- 5.3. Disorders of Branched-Chain Amino Acid Metabolism.- 5.4. ?-Methylcrotonic Aciduria.- 5.5. Disorders of Propionate, Methylmalonate, and Cobalamin Metabolism.- 5.6. Disorders of Sulfa Amino Acid Metabolism.- 5.7. Renal Amino Acid Transport Disorders.- 6. Miscellaneous Biochemical Genetic Disorders of Metabolism.- 6.1. Acatalasemia.- 6.2. Chediak-Higashi Syndrome.- 6.3. Combined Immunodeficiency Disease.- 6.4. Congenital Adrenal Hyperplasia.- 6.5. Cystic Fibrosis.- 6.6. Disorders of Collagen Metabolism.- 6.7. Cystinosis.- 6.8. Disorders of Glutathione Synthesis.- 6.9. Disorders of Proline and Hydroxyproline Metabolism.- 6.10. Disorders of Folate Metabolism.- 6.11. Huntington's Chorea.- 6.12. Hypophosphatasia.- 6.13. Lysosomal Acid Phosphatase Deficiency.- 6.14. Myotonic Muscular Dystrophy.- 6.15. Orotic Aciduria.- 6.16. The Porphyrias.- 6.17. Xeroderma Pigmentosum.- 6.18. Other Miscellaneous Disorders.- 7. Addendum.- 8. References.- 8 Biochemical and Biological Problems and Pitfalls of Cell Culture for Prenatal Diagnosis.- 1. Introduction.- 2. Biological Problems in Amniotic Fluid Cell Culture.- 3. Biochemical Pitfalls in the Use of Cultivated Aminiotic Fluid Cells for the Diagnosis of Inborn Errors of Metabolism.- 4. References.- 9 Prenatal Diagnosis of Neural Tube Defects.- 1. Introduction.- 2. Etiology.- 3. Biology of ?-Fetoprotein.- 4. Amniotic Fluid ?-Fetoprotein.- 4.1. Published Experience.- 4.2. Boston Experience.- 4.3. Twins.- 4.4. False-Positive and -Negative Results.- 4.5. Elevated AFP Concentrations in the Absence of Neural Tube Defects.- 5. Problems and Pitfalls.- 5.1. Ultrasound Prior to Amniocentesis.- 5.2. Fetal Blood Contamination of Amniotic Fluid.- 5.3. Assay Sensitivity.- 5.4. Aspiration of Urine.- 5.5. Routine AFP Assays.- 6. Other Techniques to Detect Neural Tube Defects.- 6.1. Amniotic Fluid Macrophages.- 6.2. Brain-Specific Protein.- 6.3. High-Molecular-Weight Proteins.- 6.4. ?-Trace Protein.- 6.5. Fibrinogen Degradation Products.- 6.6. Glucose.- 6.7. Proteins.- 6.8. 5-Hydroxyindoleacetic Acid (5-HIAA).- 6.9. Amino Acids.- 7. Maternal Serum ?-Fetoprotein Screening.- 7.1. Maternal Serum AFP Screening Studies.- 7.2. Miscellaneous Causes of Elevated Maternal Serum AFP Concentrations.- 8. Policy Considerations for Maternal Serum AFP Screening.- 9. Costs and Benefits.- 10. Patient and Family Considerations.- 11. Addendum.- 12. References.- 10 Diagnosis of Fetal Abnormalities by Ultrasound.- 1. Introduction.- 2. Ultrasound Imaging Techniques.- 2.1. Static B Scanning.- 2.2. Real-Time Scanning.- 3. Use of Ultrasound in Prenatal Diagnosis.- 3.1. Enhancement of the Safety and Effectiveness of Amniocentesis.- 3.2. Diagnosis of Multiple Pregnancy.- 3.3. Accurate Assessment of Fetal Age.- 3.4. Detection of Abnormal Fetal Growth.- 3.5. Detection of Changes in Amniotic Fluid Volume.- 3.6. Direct Diagnosis of Structural Fetal Abnormalities.- 4. Comparison with Amniotic Fluid AFP.- 5. Other Major Structural Defects.- 6. References.- 7. Additional References.- 11 Radiographic Fetal Diagnosis.- 1. Introduction.- 2. Abnormalities of the Head and Spine.- 3. Other Skeletal Abnormalities.- 4. Abnormalities of Other Organ Systems.- 5. Conclusions.- 6. Addendum.- 7. References.- 12 Fetoscopy and Fetal Blood Sampling.- 1. Introduction.- 2. Background.- 3. Technique of Fetoscopy.- 3.1. General Method.- 3.2. Fetal Skin Biopsy by Fetoscopy.- 3.3. Blood Sampling by Fetoscopy.- 3.4. Risks of Fetoscopy.- 4. Technique of Placental Aspiration.- 4.1. Blood Sampling.- 4.2. Risks of Placental Aspiration.- 5. Diagnosis by Fetoscopy.- 5.1. Fetal Anatomy in Preabortion Pregnancies.- 5.2. Anatomical Diagnoses in Continuing Pregnancies.- 5.3. Potential for Visual Diagnosis with Fetoscopy.- 6. Diagnosis by Biopsy.- 7. Diagnosis from Electrical Activity.- 8. Diagnosis by Fetal Blood Sampling.- 8.1. Hemoglobinopathies.- 8.2. Muscular Dystrophies.- 8.3. Hemophilias.- 8.4. Chronic Granulomatous Diseases.- 8.5. Potential for Diagnosis Using Fetal Blood.- 9. Therapy.- 10. References.- 13 Utilization of Trophoblast for Early Prenatal Diagnosis.- 1. Introduction.- 2. The Trophoblast in Vivo.- 3. The Trophoblast in Vitro.- 4. Alternatives to Amniocentesis.- 4.1. Deported Trophoblast.- 4.2. Transabdominal Intraplacental Needle Biopsy.- 4.3. Transcervical Hysteroscopic Vacuum Biopsy.- 4.4. Transcervical Blind Vacuum Biopsy.- 4.5. Sex Detection by Y-Body Analysis.- 4.6. Obtaining Trophoblast for Tissue Culture.- 4.7. Phase Contrast Analysis of Cells in the Endocervical Samples.- 4.8. Isolation of ACE Tissue from Abortus Specimens.- 5. References.- 14 Fetal Cells in the Maternal Circulation: Prenatal Diagnosis by Cell Sorting Using a Fluorescence-Activated Cell Sorter (FACS).- 1. Introduction.- 2. Fetal Cells in the Maternal Circulation.- 2.1. Frequency and Kinetics.- 2.2. Characteristics of Fetal Cells in the Maternal Blood.- 3. Prenatal Diagnosis by Cell Sorting.- 4. Addendum.- 5. References.- 15 Diagnosis, Treatment, and Prevention of Isoimmune Hemolytic Disease of the Fetus.- 1. Introduction.- 2. Counseling the Sensitized Patient.- 3. Management.- 4. Prevention.- 5. References.- 16 Role of Infectious Agents in Birth Defects: An Overview of Still-Unresolved Problems.- 1. Introduction.- 2. Agents Associated with Infection of the Fetus and Newborn.- 3. Problems in Antenatal Diagnosis and Management.- 3.1. Diagnosis.- 3.2. Prevention and Therapy.- 4. References.- 17 Elective Abortion: Techniques, Risks, and Complications.- 1. Introduction.- 2. Timing of Abortions.- 3. Techniques.- 3.1. Surgical Evacuation.- 3.2. Induction of Uterine Contractions.- 3.3. Cervical Dilatation.- 4. Conclusions.- 5. Addendum I.- 6. Addendum II.- 7. References.- 8. Additional References.- 18 Medicolegal Aspects of Prenatal Diagnosis.- 1. Introduction.- 2. Developments in the Law.- 2.1. The Right to Obtain an Abortion.- 2.2. Informed Consent.- 2.3. The Fetus and the Law.- 3. Liability of Physicians for the Birth of Children.- 3.1. The Tort of Wrongful Birth.- 3.2. The Tort of Wrongful Life.- 3.3. Implications for Prenatal Diagnosis.- 4. Addendum.- 4.1. The Tort of Wrongful Birth.- 4.2. The Tort of Wrongful Life.- 5. References.- 19 The Morality and Ethics of Prenatal Diagnosis.- 1. Moral Problems and Ethical Issues.- 2. Moral Problems in Prenatal Diagnosis.- 2.1. Risks of Amniocentesis.- 2.2. Selective Abortion.- 2.3. Indications for Prenatal Diagnosis.- 2.4. Special Problems in Selective Abortion.- 2.5. Prenatal Diagnosis, Selective Abortion, and the Defective Neonate.- 3. Ethical Issues of Prenatal Diagnosis.- 3.1. The Abortion Issue.- 3.2. The Future of Prenatal Diagnosis and Genetic Therapies.- 4. Addendum.- 5. References.- 6. Additional References.- 20 Prenatal Diagnosis and Public Policy.- 1. Introduction and Summary.- 2. Analytic Perspectives.- 2.1. The Role of Analysis.- 2.2. Risks.- 2.3. The Government-Constraints, Costs, and Benefits.- 2.4. Public Funds.- 2.5. Earnings.- 2.6. Personal Gains.- 2.7. The Gene Pool.- 2.8. The Results of Analysis.- 2.9. The Issue of Abortion.- 3. The Value of Prenatal Diagnosis.- 3.1. The Information Value.- 3.2. Mathematical Formulation.- 3.3. Interpreting the Formulation of Value.- 3.4. Setting Cutoff Points.- 4. The Context of Prenatal Diagnosis.- 4.1. The Structure of Tests.- 4.2. Evaluation.- 4.3. The General Solution.- 4.4. Action.- 4.5. Anxiety.- 5. Governmental Support for Prenatal Screening.- 5.1. Overview.- 5.2. Voluntarism and its Consequences.- 5.3. Differentiation by Means and Risk.- 5.4. Ethnic Dimensions to Risk.- 5.5. Sex Determination.- 6. Institutions and the Implementation of Policy.- 6.1. Money.- 6.2. Knowledge.- 6.3. Support.- 6.4. Ancillary Activities.- 7. Conclusion.- 8. Appendix: Carrier Screening Compared with Universal Amniocentesis for Autosomal Recessive Disease.- 9. References.