Genetic disorders and the fetus : diagnosis, prevention, and treatment

Cover
Title Page
Copyright
Contents
Preface
Acknowledgments
Contributors
Chapter 1 Genetic Counseling: Preconception, Prenatal, and Perinatal
	The burden of genetic disorders and congenital malformations
	Incidence and prevalence of genetic disorders and congenital malformations
	Congenital malformations and infant morbidity and mortality
		Down syndrome
	The goal and purpose of prenatal diagnosis
	Prerequisites for genetic counseling
		Knowledge of disease
		Expertise in genetic counseling
		Ability to communicate
		Knowledge of ancillary needs
		Empathy
		Sensitivity to parental guilt
	Guiding principles for genetic counseling
		Accurate diagnosis
		Nondirective counseling
		Concern for the individual
		Truth in counseling
		Confidentiality and trust
		Timing of genetic counseling
		Parental counseling
		Counselee education
		Duty to recontact
		Do no harm
		Duty to warn
	Preconception genetic counseling
		Indications for preconception genetic counseling
		Identification of preconception options
	Genetic counseling as a prelude to prenatal diagnosis
		Informed consent
		Presymptomatic or predictive testing
		Expansion mutations and anticipation
	Disorders with anticipation
	Disorders with suspected anticipation
		Imprinting and uniparental disomy
		Genotype–phenotype associations
		Somatic mosaicism
		Genetic counseling when the fetus is affected
		Decision making
		Elective abortion: decision and sequel
		Testing the other children
	Perinatal genetic counseling
		Family matters
		The surviving children
	The efficacy of genetic counseling
	References
Chapter 2 Preimplantation Genetic Testing
	Approaches to preimplantation genetic testing
		Polar body‐based preimplantation genetic testing
		Preimplantation genetic testing based on embryo biopsy
		Prospects for noninvasive preimplantation genetic testing
	Preimplantation genetic analysis
		Single‐gene disorders
		De novo mutations
		Late‐onset disorders
		HLA typing
		Chromosomal disorders
	Ethical and legal issues
	Conclusion
	References
Chapter 3 Amniotic Fluid Constituents, Cell Culture, and Neural Tube Defects
	Introduction
	Amniotic fluid
		Formation and circulation
		Volume
		Origin
		Biochemical and other characteristics of amniotic fluid
		Cell‐free DNA and RNA
		Proteins
		Proteomics
		Lipids
		Enzymes
		Amino acids
		Disaccharidases
		Miscellaneous biochemical constituents and other characteristics of amniotic fluid
		Blood group substances
		Immunoglobulins
		Antibacterial activity of amniotic fluid
		Bacteriostatic effect
		Isolation of infectious agents
		Hormones
		Drugs/toxicants
	Amniotic fluid cell culture
		Alternatives to cell culture and metaphase karyotype analysis
		Amniotic fluid cell types
		Cell culture and cell harvest
		Enhancement of amniotic fluid cell growth
		Testing and handling fetal bovine serum
		Defined growth factor supplements
		Culture failure
		Safety in the laboratory
		Mesenchymal stem cells in amniotic fluid
	References
Chapter 4 Molecular Aspects of Placental Development
	Overview
	Placental structure
	Placental development and function
		Implantation
		Angiogenesis
		Nutrient delivery
		Immune function
	Placental insufficiency
	Fetal growth restriction
		Genetic causes of fetal growth restriction
		Developmental considerations in confined placental mosaicism
		Imprinting and fetal growth restriction
	Preeclampsia
		Early diagnosis of preeclampsia
		Genetics of preeclampsia
	Genetic findings associated with molar changes in the placenta
		Complete hydatidiform mole
		Partial hydatidiform mole
	Placental mesenchymal dysplasia
	DNA methylation studies in the placenta and their clinical application
	Epigenetic studies in the placenta and environment
	The placenta as a predictor of child health
	Further considerations
	References
Chapter 5 Fetal Origins of Adult Health and Disease
	Introduction
	Epigenetics and programming
	Energy‐balance programming: under‐ and overnutrition
	Environmental toxins
	Maternal stress and anxiety
	Glucocorticoids and prematurity
	Organ‐specific programming effects
		Appetite and adiposity
		Hepatic programming
		Pancreas programming
		Cardiac programming
		Bone programming
		Brain programming
		Renal programming
		Immune system programming
		Endocrine programming
		Sexuality programming
	Conclusion
	References
Chapter 6 Maternal Serum Screening for Chromosomal Abnormalities and Neural Tube Defects
	Chromosomal abnormalities
	Neural tube defects
	Screening and prenatal diagnosis
	Widely used markers
	Additional markers
	Marker distributions in Down syndrome, neural tube defect, and unaffected pregnancies
	Risk screening for Down syndrome
	Age‐specific Down syndrome risk at term
	Down syndrome risk at the time of the test
	Down syndrome likelihood ratios
	Modeling performance of Down syndrome screening
	Established multimarker Down syndrome policies
	Model performance of neural tube defect screening
	Prospective confirmation of the Down syndrome model
	Further multimarker Down syndrome strategies
		First‐trimester Contingent test
		Additional first‐trimester ultrasound markers
		Additional first‐trimester serum markers
		First‐trimester Triple and Quad tests
		Second‐trimester Combined test
		Genetic sonogram
		Repeat measures and highly correlated markers
		Two‐sample Combined test
	Ultrasound screening for OSB
		Second‐trimester lemon and banana signs
		Second‐trimester anomaly scan
		First‐trimester anomaly scan
		First‐trimester screening
	Other Down syndrome markers
		A disintegrin and metalloprotease 12s (ADAM12s)
		Pregnancy‐specific glycoprotein‐1
		Urinary human chorionic gonadotropin species
		Serum invasive trophoblast antigen
		Serum thyroid‐stimulating hormone
	Clinical factors
		Maternal age
		Previous affected pregnancy
		Twins
		Assisted reproduction
		Maternal diabetes
		Renal transplant
		Previous false positive
		Smoking
		Ethnicity
		Maternal weight
		Other factors
	Edwards syndrome (trisomy 18)
	Other conditions associated with altered markers
		Other chromosome abnormalities
		X‐linked ichthyosis
		Smith–Lemli–Opitz syndrome
		Cornelia de Lange syndrome
		Abdominal wall defects
		Cardiac abnormalities
		Moles and placental mesenchymal dysplasia
		Fetal demise
		Adverse maternal–fetal complications of pregnancy
	Planning a program
	Conclusion
	Acknowledgments
	References
Chapter 7 Noninvasive Screening for Aneuploidy Using Cell‐Free Placental DNA
	Introduction
	Cell‐free DNA
	Performance of cell‐free DNA screening
	Sex chromosome aneuploidy
	Cell‐free DNA screening approaches
	Cell‐free DNA test failures
	False‐positive cell‐free DNA results and incidental findings
		Maternal malignancy
		Vanishing twins
	False‐negative cell‐free DNA results
	Cell‐free DNA screening for microdeletion syndromes
	Genome‐wide cell‐free DNA screening
	Pretest counseling
	Post‐test screening
	Comparison of cell‐free DNA screening to traditional screening
		Cost‐effectiveness
		Contingent screening
		Cell‐free DNA screening following a positive traditional screening test
	Use of prenatal ultrasound in the setting of cell‐free DNA
		First trimester
		Ultrasound soft markers and cell‐free DNA screening
		Discordance between fetal sex on ultrasound and cell‐free DNA screening
	Multiple gestations
	Cell‐based noninvasive prenatal testing
	Conclusion
	References
Chapter 8 Noninvasive Prenatal Diagnosis and Screening for Monogenic Disorders Using Cell‐Free DNA
	Introduction
	Biology and characteristics of cell‐free DNA in maternal blood
		Origin of fetal cell‐free DNA
		Importance of the fetal fraction
	General approaches for testing of single‐gene disorders by fetal cell‐free DNA analysis
		Identification of de novo or paternally inherited variants
		Identification of maternally inherited variants
		Laboratory techniques used for cfDNA‐based single‐gene disorder analysis
		Limitations of cfDNA‐based detection of single‐gene disorders
	Current status of noninvasive single‐gene testing by cell‐free DNA analysis
		Overview
		Noninvasive fetal sex determination
		Fetal RHD and other blood group genotyping
	Noninvasive prenatal diagnosis of monogenic disorders
		Skeletal dysplasias
		Duchenne and Becker muscular dystrophy
		Cystic fibrosis
		Spinal muscular atrophy
		Congenital adrenal hyperplasia
		Hemoglobinopathies
	Noninvasive prenatal screening using panels of single‐gene disorders by cell‐free DNA analysis
	Clinical implementation: ethical and social issues
	Summary and future directions
	References
Chapter 9 Amniocentesis, Chorionic Villus Sampling, and Fetal Blood Sampling
	Introduction
	Amniocentesis
		Prerequisites
		Timing
		Technique
		Ultrasound guidance during amniocentesis
		Amniocentesis in multiple gestations
		Rh isoimmunization in amniocentesis
		Significance of amniotic fluid discoloration
		Safety of genetic amniocentesis
		Pregnancy losses
		Early amniocentesis
		Third‐trimester amniocentesis
	Chorionic villus sampling
		Technique of chorionic villus sampling
		Complications of chorionic villus sampling
		Safety of chorionic villus sampling in multiple pregnancies
		Reliability of results from chorionic villus sampling
		Fetal abnormalities following chorionic villus sampling
	Fetal blood sampling
		Fetal hematologic disorders
		Fetal infection
		Fetal therapy
		Technique of fetal blood sampling
		Safety of fetal blood sampling
		Fetal blood sampling in multifetal pregnancies
		Fetal blood sampling in fetuses with single umbilical arteries
		First‐trimester fetal blood sampling
	Cardiocentesis
	References
Chapter 10 Prenatal Diagnosis of Neural Tube Defects
	Biology of α‐fetoprotein
	Amniotic fluid α‐fetoprotein
		Multiple pregnancy
		Causes of elevated (or low) levels of AFAFP in the absence of NTDs
	Likely mechanism/condition
		Leakage through skin
		Urinary tract leakage
		Leakage of placental origin
		Leakage of pulmonary origin
		Reduced intestinal AFP clearance or leakage
		Unknown site of “leakage”
		Problems and pitfalls
	Amniotic fluid acetylcholinesterase
		Experience with AFAChE
	Recommendations for prenatal diagnosis of NTDs using AFAFP and AChE assays
	Other techniques to detect neural tube defects
	Primary prevention of neural tube defects
		Genetic counseling
		Nutritional supplementation
	Complications and life expectancy
	References
	Additional references
Chapter 11 Prenatal Diagnosis of Chromosomal Abnormalities through Chorionic Villus Sampling and Amniocentesis
	The incidence of chromosomal abnormalities detected by conventional cytogenetics
		Data from livebirths
		Data from adult biobanks
		Data from amniocentesis
		Data from chorionic villus sampling
		Data from spontaneous abortuses
		Data from induced abortuses
		Data from stillbirths
	Indications for prenatal cytogenetic diagnosis
		Noninvasive prenatal testing and trisomy 21, trisomy 18, and trisomy 13
		Noninvasive prenatal testing and sex chromosome abnormalities
		Noninvasive prenatal testing and microdeletion syndromes
		Genome‐wide noninvasive prenatal testing
		Noninvasive prenatal testing and low fetal fraction
		The first‐trimester Combined test
		Second‐trimester maternal serum screening
		Elevated maternal serum ?‐fetoprotein
		Abnormal ultrasound findings
		The “genetic sonogram” or “anomaly scan”
		Advanced maternal age
		Advanced paternal age
		Multiple gestation pregnancy
		Carrier of a balanced structural rearrangement
		Previous child with trisomy
		Previous child with a de novo unbalanced rearrangement: isochromosome 21q and others
		Genetic variation in folate metabolism and previous child with a neural tube defect
		History of repeated fetal losses: parents' karyotype unknown
		History of fetal loss: fetal karyotype considerations
		Fetal demise, current pregnancy
		Male or female subfertility, cytogenetic causes
		Reduced ovarian complement
		Abnormal parental karyotype (other than a balanced structural rearrangement)
		Prenatal sex determination for X‐linked disorders
		Prenatal diagnosis for a nonchromosomal disorder
		Miscellaneous
	Interpretation issues: chromosome mosaicism and pseudomosaicism
		General considerations
		Diagnosing mosaicism in chorionic villus sampling
		Diagnosing mosaicism in amniotic fluid cell cultures
		Mosaicism involving gain of an autosome: data for individual chromosomes
		Autosomal monosomy mosaicism
		Mosaicism involving an autosomal structural abnormality (excluding supernumerary marker chromosomes) in CVS
		Mosaicism involving an autosomal structural abnormality (excluding supernumerary and marker chromosomes) in AFC
		Sex chromosome mosaicism in chorionic villus sampling
		Sex chromosome mosaicism in amniotic fluid cells
		Other types of mosaicism
		Guidelines for the diagnosis of mosaicism
		Genetic counseling and chromosome mosaicism
	Interpretation issues: chromosome rearrangements
		Familial structural rearrangements
		De novo structural rearrangements
		Uniparental disomy in familial and de novo rearrangements
		Summary conclusions and recommendations for chromosome rearrangements
	Interpretation issues: chromosome polymorphisms, common inversions, and other structural variations
		Polymorphisms of chromosomes 1, 9, 16, and Y
		Polymorphisms of acrocentric chromosomes
		Polymorphism of other chromosomes, “common” inversions, and translocations
		Summary conclusions and recommendations for polymorphisms and other variations
	Interpretation issues: maternal cell contamination
		Maternal cell contamination in chorionic villus sampling
		Maternal cell contamination in amniotic fluid cell culture
	Factors affecting diagnostic success rate and accuracy
		Twin pregnancy
		Mycoplasma contamination of cell cultures
		Toxic syringes or tubes
		Other causes of culture failure
	Technical standards for prenatal cytogenetics laboratories
	Error rates in prenatal cytogenetic diagnosis
	Discordance between karyotyping and molecular genetic testing
	Conclusion
	Acknowledgments
	References
Chapter 12 Prenatal Diagnosis of Sex Chromosome Abnormalities
	Incidence
	Ascertainment bias
	Patterns of inheritance
	Prenatal diagnosis
	Turner syndrome
		Diagnosis and management
		Cognitive/psychologic development
		Karyotype variations
		Prenatal counseling for Turner syndrome
		45,X mosaicism
	Klinefelter syndrome
		Clinical features and management
		Cognitive/psychologic development
		Prenatal counseling for 47,XXY
		47,X,i(Xq),Y
		47,XXY mosaicism
		48,XXYY
		48,XXXY
		49,XXXXY
		49,XXXYY
	Triple X and poly‐X syndromes
		Clinical features and medical management
		Cognitive/psychologic development
		Prenatal counseling for 47,XXX
		47,XXX mosaicism
		48,XXXX
		49,XXXXX
	47,XYY males
		Historical perspective
		Clinical features and medical management
		Cognitive/psychologic development
		Prenatal counseling for 47,XYY
		46,XY/47,XYY mosaicism
	Polysomy Y karyotypes
		48,XYYY
		49,XYYYY
		49,XXYYY
	Structural abnormalities of the X chromosome
		Xp deletions: del(Xp) or Xp2
		Xq deletions: del(Xq) or Xq2
		Xp duplications: dup(Xp)
		Xq duplications: dup(Xq)
		Isochromosome Xp: i(Xp)
		Isochromosome Xq: i(Xq)
		Marker X
		Inversion X: inv(X)
		X;autosome translocations
		X;X translocations
	Structural abnormalities of the Y chromosome
		Yp deletions: del(Yp)
		Yq deletions: del(Yq)
		Isochromosome Yp: i(Yp)
		Isochromosome Yq: i(Yq)
		Isodicentric Yp: idic(Yp)
		Isodicentric Yq: idic(Yq)
		Ring Y: r(Y)
		Marker Y: mar(Y)
		Inversion Y: inv(Y)
		Satellited Yq: Yqs
		Y;autosome translocations
		X;Y translocations
		Y;Y translocations
	Disorders of sex development
		46,XX males
		45,X males
		47,XXX males
		46,XY females
		Other sex reversal syndromes
		Ovotesticular disorders of sex development
	Conclusion
	References
Chapter 13 Prenatal Diagnosis of Chromosomal Abnormalities: From Karyotype to Microarray
	The study and impact of chromosome abnormalities in humans
	Traditional cytogenetic testing: analysis of the G‐banded metaphase
	Incidence and spectrum of chromosome abnormalities observed in prenatal diagnosis
	Rapid identification of the common aneuploidies
		Fluorescence in situ hybridization
		Quantitative fluorescence polymerase chain reaction
		Multiplex ligation‐dependent probe amplification
	Chromosome microarray analysis adds diagnostic yield over karyotyping and rapid aneuploidy techniques
	Types of microarrays
		Array comparative hybridization
		Single‐nucleotide polymorphisms arrays
	Microarray design for clinical testing
	Interpreting and reporting of CMA results
		Cytogenomic tools and tips for interpreting CNVs
	Factors affecting CMA diagnostic yield
		Number of probes on the array and CNV size cutoff
		Impact on variants of uncertain significance
		The benefit of SNPs
	CMA in routine pregnancies
	CMA in pregnancies with ultrasound anomalies
	CMA versus karyotyping: additional points to consider
	CMA and genetic counseling
	Conclusion
	References
Chapter 14 Molecular Genetics and Prenatal Diagnosis
	Diagnostic methods: use, limitations, and pitfalls
		Source of DNA for analysis
		Methods of analysis
	Clinical databases
	In silico tools
		Carrier detection
		Presymptomatic/predictive DNA tests
		Mutation detection
	Clinical caveats, cautions, limitations, and pitfalls
		Dynamic mutations and anticipation
		Mosaicism
		Imprinting and uniparental disomy
		Genotype–phenotype correlations
		Additional cautions and considerations
	Prenatal diagnosis of mitochondrial disorders
	Reporting incidental (secondary) results
	Ethical considerations in prenatal testing
	References
Chapter 15 Prenatal Diagnosis of Cystic Fibrosis
	Genetics and epidemiology
	Clinical features
	Diagnosis
	Treatment
	Discovery of the cystic fibrosis gene
		The CFTR gene and its protein product
		CFTR mutations and variants
	Genotype–phenotype correlation
	Congenital bilateral absence of the vas deferens
	Modifier genes
	Ethnic variation in mutation frequencies
	Development and implementation of public policy for CF population carrier screening and the core mutation panel
	Laboratory methods
	Expanded panels
	Outcomes of the CF carrier screening program
	Special prenatal diagnosis situations
		Positive–negative couples
		Positive family history
		Echogenic bowel
		Assisted reproduction and preimplantation diagnosis
		Newborn screening
	Future directions
	References
Chapter 16 Prenatal Diagnosis and the Spectrum of Involvement from Fragile X Mutations
	Introduction
	Epidemiology
	Clinical involvement in those with the full mutation
	Clinical phenotype in the premutation
	Pathogenesis of the premutation‐associated disorder FXTAS
		Neuropathology
		Molecular pathogenesis
	Molecular prenatal diagnosis methodology
	Preimplantation genetic testing and polar body analysis
	Neurobiologic advances and targeted treatment in the full mutation
	Genetic counseling
	Acknowledgments
	References
Chapter 17 Prenatal Diagnosis of Fetal Malformations by Ultrasound
	Introduction
	Craniospinal defects
		Neural tube defects
		Acrania–exencephaly–anencephaly sequence
		Open spina bifida
		Encephalocele
		Ventriculomegaly – hydrocephaly
		Hydranencephaly
		Holoprosencephaly
		Microcephaly
		Corpus callosum agenesis
		Posterior fossa malformations
		Mega cisterna magna
		Blake's pouch cyst
		Vermian hypoplasia
		Dandy–Walker malformation
	Fetal face
		Cleft lip and/or palate
		Micrognathia and retrognathia
	Pulmonary and thoracic abnormalities
		Congenital pulmonary airway malformation
		Congenital diaphragmatic hernia
		Pleural effusions
		Congenital high airway obstruction syndrome
		Fetal hydrops (immune and nonimmune)
	Cardiovascular defects
		Cardiac anomalies
		Ventricular septal defect
		Atrioventricular septal defect
		Transposition of the great arteries
		Tetralogy of Fallot
	Abdominal wall defects
		Omphalocele (exomphalos)
		Gastroschisis
		Body stalk anomaly
		Bladder exstrophy and cloacal exstrophy
	Gastrointestinal anomalies
		Esophageal atresia
		Duodenal atresia
		Small bowel obstruction
		Meconium peritonitis
		Abdominal cysts
	Kidneys and urinary tract anomalies
		Renal development and CAKUT
		Dilatation of the renal pelvis
		Structural kidney malformations
		Renal agenesis
		Abnormalities of pelvic migration
	Skeletal anomalies
	Nuchal translucency
	Phenotypic expression in chromosome anomalies
		Trisomy 21 – Down syndrome
		Trisomy 18 – Edwards syndrome
		Trisomy 13 – Patau syndrome
		Triploidy
		Turner syndrome
	References
Chapter 18 Prenatal Diagnosis and Management of Abnormal Fetal Development in the Third Trimester of Pregnancy
	Cardiac anomalies
		Value of the four‐chamber view in screening for congenital heart disease
		Abnormalities in four‐chamber view screening
		Hypoplastic left heart
		Functional assessment of the fetal heart
	Echogenic lung lesions
		Bronchopulmonary sequestration
		Congenital cystic adenomatoid malformation
		Congenital high airway obstruction sequence
		Hydrothorax
		Congenital diaphragmatic hernia
	Anomalies of gastrointestinal tract and abdominal wall
		Gastrointestinal obstruction
		Abdominal wall defects
	Urinary tract anomalies
		Incidence and etiology
		Diagnosis
		Fetal treatment
		Prognosis
	Central nervous system malformations
		Fetal ventriculomegaly
		Spina bifida
		Absence of cavum septum pellucidum and abnormalities in the midline
		Holoprosencephaly
		Agenesis of the corpus callosum
		Schizencephaly
		Absent cavum septum pellucidum
		Abnormalities of the posterior cranial fossa and cerebellar anomalies
		Parental counseling after diagnosis of fetal brain abnormalities
	References
Chapter 19 Prenatal Diagnosis by Fetal Magnetic Resonance Imaging
	Introduction
	MRI of the fetal central nervous system
		Technical issues
		Fetal brain MRI: when and why?
		Developing brain
		Developmental abnormalities
		CNS malformations
		Ventriculomegaly and genetic disorders
		Inborn errors of metabolism
		Subependymal cysts
		Brain injury
	MRI of non‐CNS fetal systems
		Technical issues
		Fetal neck
		Fetal chest
		Fetal abdomen and pelvis
		Urinary tract pathologies, kidney diseases, and genital malformations
		Skeletal malformations
	Conclusion
	References
Chapter 20 Prenatal Diagnosis of Skeletal Dysplasias and Connective Tissue Disorders
	Prenatal sonographic diagnosis of skeletal dysplasias
	Abnormal fetal morphology as an unexpected finding
	Molecular testing during pregnancy
	Estimating the probability of recurrence
	Achondroplasia, thanatophoric dysplasia, and hypochondroplasia (FGFR3 disorders)
		Prenatal diagnosis
	Osteogenesis imperfecta
		Prenatal diagnosis
	Disorders due to defects in type II collagen (achondrogenesis type 2, hypochondrogenesis, and spondyloepiphyseal dysplasia congenita)
		Prenatal diagnosis
	Disorders due to defects in the diastrophic dysplasia sulfate transporter gene (achondrogenesis 1B, atelosteogenesis type 2, and diastrophic dysplasia)
		Prenatal diagnosis
	Joint dislocations: Larsen syndrome and connective tissue disorders
		Prenatal diagnosis
	Marfan syndrome and Marfan overlap disorders
		Pregnancy‐related aspects and prenatal diagnosis
	Acknowledgments
	References
Chapter 21 Prenatal Diagnosis of Disorders of Carbohydrate Metabolism
	Introduction
	Glycogen storage diseases
		Type I GSD (glucose‐6‐phosphatase and glucose‐6‐phosphate translocase deficiency, von Gierke disease)
		Type II GSD (acid ?‐glucosidase deficiency, Pompe disease)
		Type III GSD (debrancher deficiency, limit dextrinosis, Cori or Forbes disease)
		Type IV GSD (branching enzyme deficiency, amylopectinosis, or Andersen disease)
		Type V GSD (muscle phosphorylase deficiency, McArdle disease, myophosphorylase deficiency)
		Type VI GSD (liver phosphorylase, Hers disease)
		Type VII GSD (phosphofructokinase deficiency, Tarui disease)
		Type IX GSD (phosphorylase b kinase deficiency)
		Glycogen synthase deficiency
		Hepatic glycogenosis with renal Fanconi–Bickel syndrome
	Disorders of galactose metabolism
		Galactosemia with transferase deficiency
		Galactokinase deficiency
		Uridine diphosphate galactose‐4‐epimerase (UDPgal‐4‐epimerase) deficiency
	Disorders of fructose metabolism
		Essential fructosuria
		Hereditary fructose intolerance (fructose‐1‐phosphate aldolase B deficiency)
	Disorders of gluconeogenesis
		Fructose‐1,6‐bisphosphatase deficiency
		Phosphoenolpyruvate carboxykinase deficiency
	Pentosuria
	Acknowledgments
	References
Chapter 22 Disorders of Metabolism of Amino Acids and Related Compounds
	Introduction
	Inborn errors of metabolism
	Amino acid disorders
		Methods of prenatal screening of amino acid disorders
		The placenta as a filter
		Maternal nutrition and amino acid disorders: potential impact on the fetus
	Intoxication disorders
		Urea cycle disorders
		Other disorders presenting with hyperammonemia or involving urea cycle intermediates
		Disorders of ornithine metabolism
		Sulfite oxidase deficiency
		Nonketotic hyperglycinemia
		Mevalonic aciduria
		4‐Hydroxybutyric aciduria (succinic semialdehyde dehydrogenase deficiency)
		Disorders of organic acids
		Other disorders of catabolism of branched‐chain amino acids
		Disorders of sulfur amino acid metabolism
	Disorders of energy production
		l‐2‐Hydroxyglutaric aciduria
		d‐2‐Hydroxyglutaric aciduria
		Glutaric aciduria type II (multiple acyl‐CoA dehydrogenase disorder)
	Very rare amino acid disorders
		Hypervalinemia (a disorder of valine metabolism)
		Hypermethioninemia due to methionine adenosyltransferase deficiency
		Combined d‐2‐ and l‐2‐hydroxyglutaric aciduria
		Methylenetetrahydrofolate reductase deficiency
		Prolidase deficiency
	Disorders of proline metabolism
	Disorders of renal amino acid transport
	In conclusion
	References
Chapter 23 The Mucopolysaccharidoses: Prenatal Diagnosis, Neonatal Screening and Emerging Therapies
	Introduction
	Disease and biochemical characteristics
		Clinical and biochemical fundamentals
		Structure and function of glycosaminoglycans
	Prenatal diagnosis
	Clinical characteristics and disease pathogenesis
		Clinical heterogeneity
		Genetic heterogeneity
		Genotype–phenotype correlations
		Mucopolysaccharidose disease pathogenesis
		Pathophysiology of disease
		Pathogenesis of MPS skeletal disease
		Pathogenesis of MPS nervous system disease
	Postnatal MPS therapeutics
	Newborn screening
	Fetal considerations
	Future directions
	References
Chapter 24 Prenatal Diagnosis of the Peroxisomal and Mitochondrial Fatty Acid Oxidation Deficiencies
	Introduction
	Mitochondrial versus peroxisomal fatty acid β‐oxidation
	Mitochondrial fatty acid β‐oxidation disorders
		Primary carnitine deficiency (OCTN2 deficiency) (OMIM 212140)
		Carnitine palmitoyl transferase‐1 A deficiency (OMIM 600528)
		Carnitine–acylcarnitine translocase deficiency (OMIM 212138)
		Carnitine palmitoyl transferase 2 deficiency (OMIM 600649, 600650, 255110, 608836)
		Very long‐chain acyl‐CoA dehydrogenase deficiency (OMIM 201475)
		Medium‐chain acyl‐CoA dehydrogenase deficiency (OMIM 201450)
		Mitochondrial trifunctional protein deficiency (OMIM 600890)
	Secondary disorders of mitochondrial fatty acid oxidation
	Peroxisomal fatty acid β‐oxidation disorders
	Primary peroxisomal fatty acid oxidation disorders
		X‐linked adrenoleukodystrophy (OMIM 300100)
		Acyl‐CoA oxidase 1 deficiency (OMIM 264470)
		Acyl‐CoA oxidase 2 deficiency (OMIM 601641)
		D‐bifunctional protein deficiency (OMIM 261515)
		Sterol carrier protein X deficiency (OMIM 613724)
		2‐Methylacyl‐CoA racemase deficiency (OMIM 604489)
		PMP70 deficiency (OMIM 170995) and ACBD5 deficiency (OMIM 616618)
	Secondary disorders of peroxisomal fatty acid oxidation
	References
Chapter 25 Prenatal Diagnosis of Disorders of Lipid Metabolism
	Introduction
	Lipoprotein‐associated disorders
	Defects in the metabolism of glycosphingolipids
		Structure of glycosphingolipids
		Function and distribution of glycosphingolipids
		Biosynthesis of glycosphingolipids
		Defects in the biosynthesis of glycosphingolipids
		The lysosomal catabolism of glycosphingolipids
	GM1‐gangliosidosis/mucopolysaccharidosis IVB (Morquio B)
	GM2‐gangliosidoses
		Tay–Sachs disease: mutations in HEXA gene (?‐subunit) (OMIM: 272800)
		B1 variant
		Pseudodeficiency
		Hexosaminidase S
		Sandhoff disease: mutations in HEXB (β‐subunit) (GM2‐gangliosidosis 0 variant) (OMIM: 268800)
		Variant AB
	Fabry disease
	Gaucher disease
	Metachromatic leukodystrophy
	Multiple sulfatase deficiency
	Krabbe disease (globoid cell leukodystrophy)
	Niemann–Pick disease
		Niemann–Pick disease types A and B (acid sphingomyelinase deficiency)
		Niemann–Pick type C
	Farber disease
	Lysosomal acid lipase deficiency: Wolman disease and cholesteryl ester storage disease
	The neuronal ceroid lipofuscinoses
	Acknowledgments
	References
Chapter 26 Prenatal Diagnosis of Primary Immunodeficiency Diseases
	Family history
	Specific immune defects
	Lymphocyte deficiencies
		T‐cell and combined deficiencies
	Antibody deficiencies
	Phagocyte deficiencies
	Defects with autoimmunity or immune dysregulation
	Complement deficiencies
	Additional syndromic immune defects
	References
Chapter 27 Prenatal Diagnosis of the Hemoglobinopathies
	Introduction
	Clinical types
	?‐Thalassemia
		Hb Bart's hydrops fetalis syndrome
		Hb H disease
	β‐Thalassemia
		β‐Thalassemia major
		β‐Thalassemia intermedia
	Hb E disorders
		Hb E/β‐thalassemia
		Hb AE Bart's disease
		Hb EF Bart's disease
		Hb E/E plus ?CS?/?CS?
	Sickle cell disorders
		Sickle cell anemia
		Hb S/β‐thalassemia
		Hb S/fδβ‐thalassemia
		Hb S/Hb C
		Hb S/Hb E
		Hb S/Hb D‐Punjab
		Hb S/Hb O‐Arab
		Hb S/Hb C‐Harlem
		Hb S/Hb S‐Southend
		Hb S‐Antilles
		Hb S‐Oman
		Other sickling variants
		Hb S/other rare β‐chain variants
	Carrier screening
		Reduced red cell indices with a raised Hb A2 value
		Reduced red cell indices with a normal Hb A2 value
	Strategy for fetal diagnosis
	Approaches to prenatal diagnosis
		Amniotic fluid DNA
		Chorionic villus DNA
		Noninvasive prenatal diagnosis
		Preimplantation diagnosis
	DNA diagnosis of the hemoglobinopathies
		?‐Thalassemia
		β‐Thalassemia
		The δβ‐thalassemias, Hb Lepore, and hereditary persistence of fetal hemoglobin disorders
	Abnormal hemoglobins
		Hb S
		Hb C
		Hb D‐Punjab and Hb O‐Arab
		Hb E
	Diagnostic pitfalls and best practice for fetal diagnosis
		Maternal DNA contamination
		Technical errors
		Diagnostic error rate
		Guidelines for best practice
	Summary
	References
Chapter 28 Prenatal Diagnosis of Inherited Disorders of Folate and Cobalamin Metabolism
	Inborn errors of folate metabolism
		Hereditary malabsorption of folate
		Cerebral folate deficiency
		Glutamate formiminotransferase deficiency
		Methylenetetrahydrofolate reductase deficiency
		Dihydrofolate reductase deficiency
		MTHFD1 deficiency
		Methenyltetrahydrofolate synthetase deficiency
	Inborn errors of cobalamin metabolism
		Disorders of cobalamin uptake
		Transcobalamin deficiency
		Transcobalamin receptor deficiency
		Disorders of cobalamin utilization
		Isolated methylmalonic aciduria
		Isolated methylcobalamin deficiency
		Combined methylmalonic aciduria and homocystinuria
	Prenatal diagnosis and fetal therapy
	References
Chapter 29 Fetal Surgery
	Introduction
	Brief history of fetal surgery
	Ethical considerations
	Imaging principles for fetal intervention and surgical procedures
	Control of fetal pain
	Closed fetal therapies
	Conditions treated using fetoscopic procedures
		Placental laser photocoagulation for twin‐to‐twin transfusion syndrome
		Placental laser photocoagulation for twin anemia polycythemia sequence
		Placental laser photocoagulation in monochorionic diamniotic twin pregnancies with selective fetal growth restriction
	Congenital diaphragmatic hernia
	Tracheal occlusion in human fetuses
	Urinary tract obstruction
	Fetal pleural effusion
	Congenital cystic adenomatoid malformation
	Other conditions treated with fetoscopic procedures
		Amniotic band syndrome
		Vasa previa
		Chorioangioma
	Selective termination in monochorionic gestation
	Open fetal surgery technique and complications
	Conditions treated with open fetal surgery
		Myelomeningocele
		Sacrococcygeal teratoma
	Other potentially beneficial fetal interventions
		Congenital heart defect interventions
		Ex utero intrapartum treatment
	Recent advances in fetal surgery
		Complex fetoscopic surgery
	References
Chapter 30 In Utero Stem Cell Transplantation, Enzyme Replacement, and Gene Therapy
	Introduction to in utero therapy
	In utero hematopoietic stem cell transplantation
		Background and preclinical studies
		Preclinical studies in large‐animal models
		Clinical studies
		Future of in utero hematopoietic stem cell transplantation
	In utero enzyme replacement therapy
		Background
		Preclinical studies
		Clinical studies
		Future of in utero enzyme replacement therapy
	In utero gene therapy
		Background
		Risks of in utero gene therapy
		Preclinical studies of in utero gene therapy
		Clinical studies of in utero gene therapy
	Conclusions
	References
Chapter 31 Maternal Genetic Disorders That Affect Fetal Health
	Introduction to inherited metabolic disorders
	A genetic disorder with a teratogenic effect on the fetus: phenylketonuria
	Genetic disorders precipitated by catabolic states including the late third trimester, intrapartum, and the puerperium: disabled protein breakdown
		Urea cycle disorders
		Other disorders of amino acid metabolism
		Organic acid disorders of protein metabolism
	Disorders of energy metabolism aggravated by maternal–fetal anabolic states
		Disorders of fatty acid and lipid metabolism
		Sphingolipidoses
		Disorders of carbohydrate metabolism
	Disorders of metal metabolism
		Wilson disease
	Connective tissue disorders
		Ehlers–Danlos syndrome
		Marfan syndrome
		Loeys–Dietz syndrome
	Maternal skeletal dyplasias (chondrodystrophies)
		Turner syndrome (monosomy X)
		Cystic fibrosis
	Neuromuscular disorders
		Myotonic dystrophy
		Duchenne/Becker muscular dystrophy
	Hematologic disorders
		Sickle cell disorders
		Fanconi anemia
		Hereditary coagulopathies and inherited platelet disorders
	References
Chapter 32 Pregnancy Termination for Genetic Disorders: Indications and Complications
	Introduction
	First‐trimester pregnancy termination techniques
		Suction aspiration
		Medical abortion
	Second‐trimester techniques
		Dilation and evacuation
		Systemic abortifacients
		Intra‐amniotic abortifacients and hysterotomy/hysterectomy
	Selective abortion/fetal reduction in multiple gestations
		First‐trimester selective fetal reduction
		Second‐trimester selective fetal reduction
		Counseling patients about multifetal pregnancy selective reduction procedures
	Conclusions
	Acknowledgments
	References
Chapter 33 Providing Supportive Psychosocial Care to Parents after Perinatal Loss
	Introduction
	Perinatal Loss
	Complex grief after perinatal loss
	Highly intense grief and associated health issues
	Termination of pregnancy for severe or lethal fetal anomaly
	Needs of healthcare providers
	Hutti Theoretical Framework of Perinatal Grief Intensity
		Reality
		Congruence
		Confront others
	Use of the Hutti Theoretical Framework in clinical practice
	Perinatal Grief Intensity Scale
	Communicating bad news to parents
	Preparing parents for the experience of perinatal loss
	Labor and birth
	After hospital discharge
	Subsequent pregnancy
	Interventions for high‐quality perinatal bereavement care
		Regoaling
	Conclusion
	References
Chapter 34 Prenatal Diagnosis of Fetal Infection
	Prenatal diagnosis of fetal toxoplasmosis
		Parasitology
		Epidemiology
		Risk factors
		Prenatal diagnosis
		In utero therapeutic options
		Management at birth
		Prevention of fetal toxoplasmosis: education
		Summary
	Prenatal diagnosis of fetal cytomegalovirus infection
		Virology
		Epidemiology
		Pathogenesis of congenital infection
		Pathology
		Congenital infection
		Clinical maternal manifestations
		Serology
		Management
		Diagnosis of congenital CMV infection in the fetus
		Forming a prognosis for fetal CMV infection
		Treatment of congenital CMV infection
		Prevention of CMV infection
		Screening for congenital CMV infection
	Prenatal diagnosis of congenital rubella
		Risk of fetal infection
		Definition of maternal infection
		Prenatal diagnosis of fetal infection
		Summary
	Prenatal diagnosis of fetal varicella infection
		Virologic bases
		Epidemiology
		Clinical aspects of maternal infection
		Consequences for the pregnancy and the fetus
		Pathogenesis of fetal VZV infection
		Diagnosis of fetal VZV infection
		Frequency of VZV transmission
		Treatment and prevention of VZV
		Summary
	Prenatal diagnosis of human parvovirus B19 infection
		Epidemiology, maternal infection, and vertical transmission of parvovirus B19
		Prenatal diagnosis of parvovirus B19
		Treatment of parvovirus B19
	Prenatal diagnosis of Zika virus
		Maternal infection with Zika virus
		Infection of the fetus with the Zika virus
	Prenatal counseling in the midst of the SARS‐CoV‐2 pandemic
	Acknowledgments
	References
Chapter 35 Medicolegal Aspects of Prenatal Diagnosis
	General concepts of medical malpractice
	The constitutional right of privacy in reproductive decisions
	The role of informed consent in medical treatment
	Suits for wrongful birth and wrongful life
		Wrongful pregnancy – the parents' claim, usually after having a healthy, but unwanted child
		Wrongful birth – the parents' claim after having a child with a genetic disorder or congenital anomaly
		Wrongful life – the child's claim
		Wrongful life claims against the parents
	The impact of concerns about abortion on wrongful birth and wrongful life claims
	Future trends
	Summary of alleged negligent acts and outcomes in wrongful birth and wrongful life suits
	Statutes addressing claims for wrongful birth and wrongful life as well as abortion in the case of fetal anomaly
	References
Chapter 36 Prenatal and Preimplantation Diagnosis: International Policy Perspectives
	Introduction
	Prenatal diagnosis
	Legal approaches
	Professional guidelines
	Preimplantation genetic diagnosis
		Legal approach
		Professional guidelines
		Hybrid regulatory approach
	Sex selection in prenatal diagnosis and preimplantation genetic diagnosis
	Emerging technologies, new issues?
	References
Chapter 37 Ethical Issues in the Diagnosis and Management of Genetic Disorders in the Fetus
	Professional ethics in obstetrics
		The ethical principle of beneficence
		The ethical principle of respect for autonomy
		The ethical concept of the fetus as a patient
	Clinical applications of professional ethics in obstetrics
		Prenatal genetic counseling
		Diagnosis of genetic disorders in the fetus
		Preimplantation diagnosis and the “savior sibling”
		Management of pregnancies complicated by genetic disorders
	Ethical issues in clinical innovation and research
		Genomic alteration research
		Maternal–fetal medical and surgical intervention for fetal benefit innovation and research
		Human embryonic stem cell research
	Conclusion
	References
Index
EULA