CHAPTER 20 1. Define birth defects and possible causes. 2. Become familiar with genetic terminology. 3. Identify the number of chromosomes in a normal human cell. 4. Describe the characteristics and causes of structural and numeric chromosomal abnormalities, modes of inheritance of single-gene disorders, and multifactorial inheritance. 5. Describe what prenatal diagnostic tests are available and which anomalies they detect. 6. Describe the components and benefits of genetic counseling. 7. Identify three patient care management issues in genetic counseling. 8. Verbalize the systematic process used to evaluate the malformed infant. 9. List common congenital malformations and possible mechanisms of cause. The neonate born with a genetic defect or fetal anomaly presents a challenge to the neonatal intensive care unit (NICU) team. A definitive diagnosis is essential for management and care of the neonate and the neonate’s family. Congenital malformations commonly have multiple causes. This chapter includes information on basic genetics, characteristics, and causes of some common fetal anomalies, and a systematic process for the evaluation of the malformed infant. Commonalities of patient care management issues are addressed, with the understanding that every family requires individualized care. A. Allele: one of a series of alternate forms of a gene at the same locus on a chromosome (Jones, 2005; Jorde et al., 2010). B. Autosome: one of 22 chromosomes that do not determine the sex of the individual. C. Birth defect: an abnormality of structure, function, or metabolism, whether genetically determined or a result of environmental interference during embryonic or fetal life. A congenital defect may cause disease from the time of conception through birth or later in life (March of Dimes Foundation, 2008). D. Chromosome: structural elements in a cell nucleus that carry the genes and convey genetic information. 2. There are 23 pairs of chromosomes, for a total of 46 chromosomes, with one maternal and one paternal chromosome creating each pair. E. Diploid: containing a set of maternal and a set of paternal chromosomes, for a total of 46 chromosomes. F. Gamete: one of two cells, containing 23 chromosomes (haploid number), with the union of a male gamete and a female gamete required during sexual production to create a new individual (with the diploid number of chromosomes). G. Gene: the smallest unit of inheritance of a single characteristic, responsible for a physical, biochemical, or physiologic trait and located with other genes in linear sequence along the chromosome. H. Genotype: hereditary composition of an individual. I. Haploid: having half the number of chromosomes found in the person’s cells; characteristic of the gametes. J. Locus: the position that the gene occupies on a chromosome. K. Karyotype: pictorial representation of the chromosomal characteristics of an individual or species. L. Penetrance: The degree to which an inherited trait is manifested in the person who carries the affected gene (Nussbaum et al., 2007). M. Sex chromosomes: the X and Y chromosomes which are responsible for sex determination—XX for female and XY for male. A. Phenotype: observable characteristics of an individual. B. Heterogeneous chromosomes: differing pair of chromosomes, one from each parent, arraying differing genes for specific traits. When there are unlike genes on a locus, one gene dominates. C. Homologous chromosomes: a matched pair of chromosomes, one from each parent, carrying the genes for the same traits. D. Dominant gene: a gene that is expressed in the heterozygous state. In a dominant disorder, the mutant gene overshadows the normal gene. A dose of this gene is needed for expression. E. Recessive gene: a gene whose effect is masked or hidden unless both genes of a set of homologous chromosomes at a given locus are abnormal, thus showing the disease. In a heterozygote (carrier), the normal gene overshadows the mutant gene. F. Possible combinations of chromosomes. 1. Both genes can be dominant—AA (homozygous). 2. Both genes can be recessive—aa (homozygous). 3. One gene can be dominant and one can be recessive—Aa (heterozygous). A. Autosomal dominant disorders. 1. Characteristics of autosomal dominant disorders. b. An affected offspring has an affected parent if the mutation is not new. c. Half the sons and half the daughters of an affected parent can be anticipated to have the disorder. There is a 50% chance with each pregnancy. d. Unaffected offspring of an affected parent will have all normal offspring if the mate is an unaffected person (assuming complete penetrance). e. If two affected people mate, three fourths of their offspring will be affected. A double dose of the mutant gene in any of the offspring will result in a lethal anomaly (except in the case of Huntington’s disease). f. Family history of an anomaly indicates a vertical route of transmission through successive generations on one side of the family (if not a new mutation). 2. Examples of autosomal dominant disorders: myotonic dystrophy, neurofibromatosis, and coronary artery disease (Allanson and Cassidy, 2010; Jones, 2005). B. Autosomal recessive disorders. 1. Characteristics of autosomal recessive disorders. a. Both males and females are affected equally. b. Parents of affected offspring are rarely affected and are usually heterozygous carriers. c. After the birth of an affected offspring, there is a 25% chance, with each pregnancy, of having another affected offspring and a 50% chance that the offspring will be a carrier. d. There may be a distant relative with the disorder. e. Affected people who mate with unaffected people will have offspring who will be heterozygous carriers. f. If two affected people mate, all offspring will be affected. g. No family history indicates a horizontal route of transmission in the same generation. h. There can be a difference in expression of the disorder: very mild in one member and extremely severe in another. 2. Examples of autosomal recessive disorders: cystic fibrosis, sickle cell anemia, Tay–Sachs disease, thalassemia major (Jones, 2005). A. X-linked dominant disorders. 1. Characteristics of X-linked dominant disorders. b. Affected males will have all affected daughters and no affected sons. c. Affected females will transmit the disorders in the same manner as with autosomal dominant patterns. d. Two thirds of the time, affected females have an affected mother; one third of the time, they have an affected father. e. Family history shows no father-to-son transmissions. 2. Example: vitamin D–resistant rickets. B. X-linked recessive disorders. 1. Characteristics of X-linked recessive disorders. b. Carrier females transmit the disorder. c. All sons of affected males will be normal. d. All daughters of affected males will be carriers (with each pregnancy). e. Heterozygous females transmit the gene to half their sons, who will be affected, and to half their daughters, who will be carriers. f. Transmission is horizontal among males in the same generation; in addition, a generation will be skipped, and second-generation males will be affected. 2. Examples: Duchenne’s muscular dystrophy, hemophilia, color blindness, and glucose-6-phosphate dehydrogenase deficiency (Kingston, 2002). B. Because of the unique properties of mitochondria, these diseases display characteristic modes of inheritance and a large degree of phenotypic variability (Jorde et al., 2010). C. The mitochondria, which produce adenosine triphosphate (ATP), have their own unique deoxyribonucleic acid (DNA). Mitochondrial DNA (mtDNA) is maternally inherited and has a high mutation rate. A number of diseases are known to be caused by mutations in mtDNA. D. Organ systems with large ATP requirements and high thresholds tend to be the ones most seriously affected by mitochondrial diseases; for example, the central nervous system (CNS) consumes 20% of the ATP the body produces and is often affected by mtDNA mutations. E. Mitochondrial mutations are also involved in some common human diseases, for example, a form of deafness (Jorde et al., 2010). B. Nonmultiples are designated by the suffix “-somy”; monosomy is one less than the diploid number (45), and trisomy is one more than the diploid (47). C. Causes. 1. Nondisjunction: failure of paired chromosomes to separate during cell division. 2. Chromosome lag: failure of a chromosome to travel to the appropriate daughter cell. 3. Anaphase lag: chromosome lag during the third state of division of a cell nucleus in meiosis and mitosis. 4. Mosaicism: nondisjunction of an anaphase lag that occurs during mitosis after fertilization, resulting in two different cell lines in the same person (Jones, 2005). A. Deletion: loss of a chromosomal segment. B. Duplication: any duplication of a region of DNA that contains a gene. It is a process that can result in a new mutation. C. Translocation: occurrence of a chromosomal segment at an abnormal site, either on another chromosome or in the wrong position on the same chromosome (i.e., an inversion). D. Inversion: occurs when a segment of the chromosome breaks off and reattaches in the reverse direction. E. Nonreciprocal translocation: a one-way transfer of a chromosomal segment to another chromosome. F. Polygenic defects: type of inheritance in which a trait is dependent on many different gene pairs with cumulative effects. G. Environmental influences. Inadequate nutritional intake, certain drugs, irradiation, and viruses are examples that could alter the genetic makeup of an offspring while in vitro. Multifactorial: genes plus environment. H. Basic generalizations. 1. Loss of an entire autosome is usually incompatible with life. 2. One X chromosome is necessary for life and development. 3. If the male-determining Y chromosome is missing, life and development may continue but will follow female pathways. 4. Extra entire chromosomes, the translocation of extra chromatin material, and the insertion of extra chromatin material are often compatible with life and development. 5. Multiple congenital structural defects are present when gross aberrations are present (Blackburn, 2012). I. Incidence. 1. Autosomal aberrations: 5 in 1000 births. 2. Sex chromosome aberrations: 2 in 1000 births. 3. Spontaneous abortions: 60% are associated with chromosomal aberration (Jorde et al., 2010). Recent technological advances and marked progress in the understanding of the etiology and pathogenesis of many common disorders have allowed many families a prenatal diagnosis. 2. Prior child with a chromosomal disorder. 3. Family history of neural tube defects. 4. Previous child with multiple malformations. 5. Carriers of X-linked diseases. 6. Carriers of chromosome translocation. 7. Couples at risk of having a child with a specific inborn error of metabolism (previous child or by carrier testing). 8. Ultrasonographic identification of major malformation, polyhydramnios, and/or intrauterine growth restriction (Jorde et al., 2010). B. Advantages. 1. Knowledge that the fetus is unaffected. 2. Time to explore options and prepare for an affected newborn infant. 3. Opportunity electively to choose either to avoid starting a pregnancy or to abort an affected fetus. 4. Opportunity for the physician to plan delivery, management, and care of the infant when the disease is diagnosed in the fetus (Jorde et al., 2010). 2. Human chorionic gonadotropin is a hormone produced by the placenta. Levels rise in maternal blood for the first trimester of pregnancy and then fall to less than 10% by the end of pregnancy. 3. Unconjugated estriol is a form of estrogen that is produced by the fetus through metabolism. This process involves the liver, the adrenals, and the placenta. Some of the uE3 crosses the placenta and can be measured in the mother’s blood. Levels rise around the eighth week and continue to increase until shortly before delivery. 4. Inhibin A is a hormone also produced by the placenta. Inhibin is a dimer (has two parts) and is sometimes referred to as DIA or dimeric inhibin A. Levels in maternal blood decrease slightly from 14 to 17 weeks of gestation and then rise again. B. Screening test, not a diagnostic test. Abnormal result does not indicate an abnormality but will indicate the possible need for a diagnostic test to rule out abnormalities. 1. Trisomy 21: the levels of AFP and uE3 tend to be low and hCG and inhibin A levels high. 2. Trisomy 18: the levels of uE3 and hCG levels are low and AFP levels are variable. 3. Open neural tube defects: where there is an opening in the infant’s spine, head, or abdominal wall that allows higher than usual amounts of AFP to pass to the mother’s blood. C. Shortfalls of this test. 2. In multiple-gestation pregnancies, calculation of the risk of trisomy 21 or trisomy 18 is difficult. For twin pregnancies, a “pseudo-risk” can be calculated comparing results to normal results in other twin pregnancies. For higher gestation pregnancies, risk cannot be calculated from these tests. 3. Evaluation of the risk of open neural tube defects in twin pregnancies can be determined, although it is not as effective as in singleton pregnancies. D. Results and further testing: A multiple marker test or triple screen is used to determine if a fetus is at an increased risk of having certain congenital abnormalities. The test has a high rate of false positives; as few as 10% of women with abnormal results go on to have babies with congenital defects. The purpose of the test is to determine if further testing (such as ultrasound or amniocentesis) is warranted. B. Initial assessment recommended by 16 to 20 weeks of gestation for the verification and evaluation of gestational age. C. Ultrasonography: to detect abnormalities of fetus, placenta, amniotic fluid, and uterus; to monitor changes in anatomy and growth with serial ultrasonography. D. Diagnostic capability: only as good as the person’s training—not just contingent on the equipment. E. No known harmful effects. F. Critical to safety of amniocentesis: chorionic villus sampling and percutaneous blood sampling. G. Anatomic landmarks commonly observed: fetal spine, kidneys, bladder, stomach, three-vessel cord, cord insertion, four-chambered heart, face, upper lip, biparietal diameter, head circumference, abdominal circumference, femur length, transcerebellar diameter, placenta, amount of amniotic fluid, uterus, and adnexa. H. Detectable anomalies: many, including those indicative of various syndromes. Examples: anencephaly, atrial septal defect, cardiac anomalies, choroid plexus cyst, cleft lip, craniosynostosis, cystic hygroma, cystic kidneys, encephalocele, gastroschisis, hydrocephalus, microcephaly, myelomeningocele, omphalocele, skeletal dysplasia (Jorde et al., 2010). B. Procedure. Normal results of amniocentesis do not guarantee a good fetal outcome. Obtain mother’s blood type before procedure. If she is Rh negative, obtain father’s blood type. C. Usual timing of procedure: 16 to 18 gestational weeks, but amniocentesis can be performed later in gestation and as early as 14 weeks. D. Indications. 1. Woman of advanced maternal age (> 35 years at the time of expected delivery). 2. Previous fetus with Down syndrome. 3. Previous fetus with neural tube defect. 4. Both parents known as heterozygous carriers of autosomal recessive chromosome. 5. Both parents known as carriers of sex-linked recessive disorder. 6. Client or partner with balanced chromosomal translocation of his or her chromosomes. 7. A woman with an abnormal triple or quad screen. E. Fluid analysis: requires 2 to 3 weeks for cells to grow adequately for accurate analysis. F. Risks: Overall risk to mother or fetus is 1%. 1. Spontaneous abortion: approximately 0.5% of cases. 2. Hemorrhage. 3. Infection. 4. Premature labor. 5. Rh sensitization from fetal bleeding into maternal circulation. 6. Trauma to fetus or placenta. G. Analysis. 2. α1-Fetoprotein: abnormally high or low levels raise concern (see earlier section on triple and quad screening, under Prenatal Tests). 3. Biochemical: metabolism disorders, including Tay–Sachs disease (a lipid disorder) and amino acid, carbohydrate, and mucopolysaccharide metabolism disorders, can be discovered by 20 weeks of gestation. 4. Chromosomes: abnormalities, including Down syndrome, other trisomies, and other chromosomal abnormalities, can be detected at 16 weeks of gestation by karyotyping. H. Postamniocentesis care. 1. It is important that the mother receive immune globulin (RhoGAM) if she is Rh negative and if father of fetus is either Rh positive or of unknown blood type. Do not give RhoGAM if Rh sensitization has occurred (Jenkins and Wapner, 2008). B. Preparation: Review risks and benefits of the procedure, discuss options, and arrange to obtain CVS results. Obtain written consent for this procedure. C. Timing of procedure: usually 8 to 10 weeks of gestation. D. Indications. 1. Mother prefers to make decisions regarding pregnancy in the first trimester. 2. Severe oligohydramnios. E. Contraindications. 2. Uterine bleeding during this pregnancy. 3. Active genital herpes infection or other cervical infection. 4. Uterine fibroids. F. Fetal cell analysis: requires 24 to 48 hours for initial results. G. Risks: overall, 2% to 3%. 2. Bleeding. 3. Cervical lacerations. 4. Miscarriage: 1% to 5%. H. Techniques of CVS. 2. Abdominal CVS: Needle is inserted through the abdomen into the chorion to obtain a sample of the chorionic villi. I. Post-CVS care. B. Preparation: same as that recommended for CVS. C. Timing: 18 weeks to term. D. Indications. 1. Mother wants fast results to support her decision making regarding pregnancy. 2. Abnormality is identified by ultrasonography late in pregnancy. 3. Mother has been exposed to infectious disease that could affect development of fetus. 4. Blood incompatibility (Rh disease). 5. Drug or chemical level in fetal blood needs to be assessed. E. Risks. 2. Perforation of uterine arteries, clotting in fetal cord. 3. Premature delivery. F. Results: fetal blood analysis takes 3 days. G. Postsampling care: same as postamniocentesis care (Drugan et al., 2005). B. High-resolution banding/prometaphase banding: Some disorders cannot be seen reliably on standard chromosome analysis and require special handling during processing. Prometaphase banding is used because the cell growth during culturing is adjusted to maximize the number of cells in prometaphase, where the chromosomes are much less condensed and therefore longer, rather than in metaphase, where the cell growth is stopped in standard chromosome studies. High-resolution banding can have from 550 to 800 bands and allows a much more detailed analysis. C. Fluorescence in-situ hybridization (FISH) is a molecular cytogenetics technique that combines chromosome analysis with the use of fluorescence-tagged molecular markers (probes) that are applied after the chromosome preparation is produced. This method relies on the phenomenon of hybridization of complementary pieces of DNA. FISH is a powerful tool useful not only in diagnosing relatively common microdeletion or microduplication disorders but also for identifying the origin of extra chromosome material (Drugan et al., 2005). D. Polymerase chain reaction (PCR) is a powerful technique in amplifying many copies of a segment of DNA so that it can be analyzed. PCR is useful in disorders with recurring mutation, for example, achondroplasia. E. Comparative genomic hybridization microarray testing: This testing is an advancement in cytogenetic technology that is used for the detection of cytogenetic imbalances that are smaller than what can be detected through routine chromosome analysis. Testing will detect the loss (deletion) or gain (duplication) of chromosomal regions. A. What is the Human Genome Project? 2. The project started in the mid-1980s and is the single most important coordinated medical research initiative in the history of biomedical research. It culminated in the completion of the full human genome sequence in April 2000 (www.genome.gov). 3. The goals of the project were to map genes on chromosomes and to determine the sequence of the nucleotides that make up human DNA, which is the basic genetic material. One of the top priorities was to generate complete sets of full-length chromosomal DNA (cDNA) clones and sequences for both human and model organism genes. It is expected that genome research will produce a ream of new information about the genes involved in inherited disorders, birth defects, and common conditions influenced by genetic factors. 4. One insight already obvious is that even on a molecular level we are more than the sum of our 35,000 or so genes. However, surprisingly this new estimated number of genes is only one third of what was previously thought, although the numbers may be revised as more analyses are performed. This suggests to scientists that the genetic key to human complexity lies not in the number of genes but in how gene parts are used to build different products in a process called alternative splicing. 5. In December 1999, the first human chromosome, chromosome 22, was sequenced. This is the location of defects that can cause DiGeorge syndrome, chronic myeloid leukemia, and neurofibromatosis. It is also the final autosome in the human sequence as outlined by the National Institutes of Health Human Genome Report in 2003 (Collins et al., 2003). 6. Though the outcome of the Human Genome Project itself is not ethically problematic, the use of the data generated presents major ethical questions that must be addressed. The future, then, presents the challenges of addressing the project’s implications (Blackburn, 2012; Larsson, 2001). B. Ethical, legal, and social issues program. 2. The program also emphasizes the importance of understanding the cultural, ethnic, social, and psychological influences that must inform policy development and service delivery issues. 3. With time, these issues must be addressed to ensure that the maximal benefit is gained from the project (Blackburn, 2012; Larsson, 2001). B. Principles of genetic counseling. 1. Based on correct diagnosis and pattern of inheritance. 2. Nondirective. 3. Reinforcement of information previously presented. 4. Emphasis on communication with the primary care physician. C. Goal of genetic counseling is to assist the family in comprehending the 2. Role of heredity. 3. Recurrence risks and options. 4. Possible courses of action. 5. Methods of ongoing adjustment. D. Indications (Blackburn, 2012; Drugan et al., 2005). 1. Previously affected child, parent, or grandparent. b. Sensory defect. c. Metabolic disorder. d. Mental retardation. e. Known or suspected chromosome abnormality. f. Neuromuscular disorder. g. Degenerative CNS disease. 2. Previously affected cousins. b. Hemophilia. c. Hydrocephalus. 3. Consanguinity. 4. Hazards of ionizing radiation. 5. Recurrent miscarriages. 6. Concern for teratogenic effect. 7. Advanced maternal age. 8. High or low maternal serum AFP. E. Methods of obtaining information needed. 2. Pedigree. 3. Medical records. 4. Physical examination. 5. Laboratory tests. 6. Carrier detection. F. Provision of medical facts. 2. Risks to fetus and mother. 3. Probable course of disorder. 4. Recommended management for prenatal course. 5. Type and timing of delivery. 6. Neonatal, pediatric, and long-term care requirements. G. Explanation of hereditary factors that contribute to the disorder. H. Discussion with parents regarding all alternatives. 1. Home care of newborn infant. 2. Institutionalization. 3. Adoption. 4. Appropriate method of termination for gestational age. 5. Objective information regarding fetal and neonatal status. Provide statistical risk factors as they relate to this individual fetus. 6. Identification of the normal characteristics that can exist in the affected fetus. Point these out in pictures to promote awareness of the total condition of the fetus. 7. Assistance to parents: understanding of causes, risks of recurrence, and limits of current treatments. 8. Discussion of options available for dealing with risk of recurrence. 9. Written information for parents and information regarding support groups. 10. Explanation of recommended obstetric care, mode and timing of delivery, and neonatal care (Jones, 2005). B. Evaluation of infant with a birth defect. A birth defect is a structural or functional abnormality of the body that is present from birth. The effects of a birth defect may be either immediate or delayed until later in life. C. Syndrome. 2. Examples: fetal alcohol syndrome, trisomy 21. D. Sequence. 2. Example: Pierre Robin sequence. Lannelongue and Menard first described Pierre Robin syndrome in 1891 in a report on two patients with micrognathia, cleft palate, and retroglossoptosis. In 1926, Pierre Robin published the case of an infant with the complete syndrome. Until 1974, the triad was known as Pierre Robin syndrome; however, the term syndrome is now reserved for those errors of morphogenesis with simultaneous presence of multiple anomalies caused by a single etiology. The term sequence has been introduced to include any condition that includes a series of anomalies caused by a cascade of events initiated by a single malformation. The initial event, mandibular hypoplasia, occurs between the seventh and 11th week of gestation. This keeps the tongue high in the oral cavity, causing a cleft in the palate by preventing the closure of the palatal shelves. This explains the classic inverted U-shaped cleft and the absence of an associated cleft lip. Oligohydramnios could play a role in the etiology since the lack of amniotic fluid could cause deformation of the chin and subsequent impaction of the tongue between the palatal shelves. E. Association. 2. Example: coloboma, heart defect, atresia choanae, restricted growth and/or development, genital anomalies, and ear anomalies (CHARGE) association. F. Malformation. 2. Examples: neural tube defects, cleft lip and palate. G. Deformation. 2. Examples: Pierre Robin sequence, uterine position defects, and oligohydramnios sequence. H. Disruption. 2. Examples: amniotic bands, vascular accidents, and infections. I. Genetic heterogeneity. 1. Definition: different causes may produce similar characteristics. 2. Examples: hydrocephalus, cleft lip and palate. 1. History of three generations. 2. Defects in the family history related to the problem in the child. 3. Medical records and/or photos of similarly affected relatives. 4. History of consanguinity. 5. Reproductive history, such as frequent spontaneous abortions. 6. Pattern of inheritance of the problems. B. Prenatal history. 2. Fetal activity level. 3. Maternal exposures: infections, illness, high fevers, medications, x-ray examinations, known teratogens, alcohol, smoking, and use of street and prescription drugs. 4. Obstetric factors: uterine malformations, complications of labor, and presenting fetal part. 5. Neonatal factors: birth weight, length, head circumference, and Apgar scores. 1. General: asymmetry, problems of relationship, and inappropriate size and strength. 2. Face: configuration; centered features with normal spacing; round, triangular, flat, birdlike, elfin, coarse, or expressionless characteristics. 3. Head: size of anterior fontanelle, prominence of frontal bone, flattened or prominent occiput, abnormalities in shape (proportionally large or small). 4. Skin: intact, or presence of skin tags, open sinuses, tracts. 5. Hair: texture, hairline, presence of whorls. 6. Eyes: structure and color of iris, presence of colobomas, centering and spacing of epicanthal folds (hypotelorism or hypertelorism), ptosis, slanting, eyelash length. 7. Ears: protruding or prominent shape, location, low-set, unilateral or bilateral defect, presence and/or degree of rotation. 8. Nose: beaked, bulbous, pinched, upturned, misshapen, number of nares, flattened bridge, patency, centered on face. 9. Oral: intact palate, presence of smooth philtrum, natal teeth; shape and size of tongue, mouth, jaw (micrognathia). 10. Neck: short and/or webbed, redundant folds. 11. Chest: symmetrical; presence of accessory nipples. 12. Abdomen: number of cord vessels, presence of abdominal wall defects and abdominal musculature, prune belly. 13. Genitourinary system (male): hypospadias—four degrees, dependent on placement of meatus; chordee; ambiguous genitalia; testes descended. 14. Anus: position, patency. 15. Spine: intact, scoliosis, lordosis, kyphosis. 16. Extremities: length, shape, absence of bones. 17. Hands and feet: broad, square, or spadelike shape; polydactyly, clinodactyly, syndactyly, abnormal creases in the palm of the hand (simian or Sydney creases), contractures, abnormally large or small size, overriding fingers, proximally placed thumb, rocker-bottom feet. B. Causation of defect. 1. Identify the primary abnormality. 2. Recognize etiologic heterogeneity (a defect having more than one cause). 3. Determine category of congenital malformation, according to etiology. b. Deformation. c. Disruption. d. Syndrome. e. Association f. Sequence. g. Genetic heterogeneity. C. Family care management for all genetic syndromes or disorders. 2. Encourage genetic counseling. 3. Facilitate family use of support systems: social services; Aid to Families with Dependent Children; Women, Infants, and Children (WIC) program; March of Dimes; clergy; mental health services; support groups; Internet information. 4. Provide unconditional emotional support. Allow parents and siblings to verbalize feelings. 5. Identify normal aspects of neonate that can coexist with the syndrome or disorder. 6. Promote parent involvement in care; offer choices in care and interventions. 7. Discuss treatment options and their risks and benefits. 8. Provide literature. 9. Obtain legal and ethical counsel when parents prefer not to pursue medical interventions (Nelson, 2012). VATER is an acronym for vertebral anomalies, anal atresia, tracheoesophageal fistula, and radial and renal dysplasia. A. Etiology and precipitating factors: unknown. B. Incidence: 1.6 in 10,000. C. Clinical presentation. Three or more of the following defects are present: 2. Anal atresia with or without fistula. 3. Tracheoesophageal fistula with esophageal atresia. 4. Radial dysplasia, including thumb or radial hypoplasia, polydactyly, and syndactyly. 5. Renal anomaly. 6. Single umbilical artery. D. Complications and outcome. 2. Possibility of normal life after slow mental development during infancy. E. Care management. 1. Supportive: Prognosis and management depend on the extent and severity of the anomalies. 2. Surgery: surgical correction of anomalies. VACTERL is an acronym for an association characterized by the sporadic, nonrandom association of specific abnormalities: vertebral abnormalities, anal atresia, cardiac abnormalities, tracheoesophageal fistula and/or esophageal atresia, renal agenesis and dysplasia, and limb defects. A. Etiology and precipitating factors. 2. Injury between 4 and 6 weeks to a specific mesodermal area may produce simultaneous anomalies of the hindgut, lower vertebral column, lower urinary tract, and developing kidney. 3. Abnormalities: average of seven or eight per patient. B. Incidence: rare (about 250 reported cases worldwide). C. Clinical presentation (Hockenberry, 2011; Jones, 2005). 2. Anal atresia with or without fistula. 3. Cardiac anomalies: commonly ventricular septal defects. 4. Tracheoesophageal fistula with or without esophageal atresia. 5. Radial dysplasia, including thumb or radial hypoplasia, polydactyly, and syndactyly. 6. Renal anomaly. 7. Single umbilical artery. D. Complications and outcome. 2. Normal life: minimal CNS anomalies with only occasional mental retardation. E. Care management (Hockenberry, 2011). 1. Supportive: Prognosis and management depend on the extent and severity of the anomalies. 2. Surgery: surgical correction of anomalies. 1. Incidence by maternal age is as follows: b. 30 to 34 years: 1 in 800 c. 35 to 39 years: 1 in 270 d. 40 to 44 years: 1 in 100 e. 45 years or older: 1 in 50 2. Accounts for 15% to 20% of cases of severe mental retardation. 3. Risk increases with maternal age. 4. 25% of Down syndrome infants receive an extra chromosome from their father. 5. Person has 47 chromosomes (3 of chromosome 21). 6. Extra chromosome fits into group G21,22. Extra chromosome results from nondisjunction during meiosis. May occur unrelated to maternal risk factors and appear as follows: b. Translocation of chromosome 21. c. Familial transmission autosomal dominant. d. No abnormalities if chromosomes are balanced. There is one no. 21 and one no. 14 chromosome. e. Production of unbalanced gametes by balanced carriers: should consider prenatal diagnosis. 7. Some infants have mosaicism for trisomy 21 or translocation 14/21 or 21/22. b. Some have only a few. c. Some of this group may have normal intellectual ability. B. Clinical presentation (Jones, 2005). 1. Size: small; 20% are premature. 2. Skull: short and round with a flat occiput. 3. Eyes: slant upward and outward. 4. Prominent epicanthal fold. 5. Flat face. 6. Brushfield’s spots: iris may be speckled with a ring of round, grayish spots or flecks of gold in light-colored eyes. 7. Cheeks: red. 8. Palate: narrow and short. 9. Nose: short with a flat nasal bridge. 10. Tongue: protrudes; can become dry and wrinkled. 11. Skin loose around lateral and dorsal aspects of the neck. 12. Hands. b. Hands: square. c. Single simian creases. 13. Feet. a. Wide space between great toe and second toe. b. Deep crease that starts between the great toe and the second toe and curves. 14. Muscular hypotonia. 15. Narrow acetabular angle. 16. Narrow iliac index. 17. Broadened iliac bones. 18. Delayed psychomotor development. 19. Cardiac ventricular septal defects or other congenital heart defects found in 50% of infants. 20. Duodenal atresia. C. Complications and outcome. 1. Congestive heart failure due to congenital heart disease. 2. Upper respiratory tract infections. 3. Delayed development: IQ ranges from 25 to 70. A. Etiology and precipitating factors. 1. Nondisjunction most frequent; also possible partial trisomy, translocation, or mosaicism. 2. Advanced parental age. B. Incidence: 1 in 3500 births. C. Clinical presentation.Characteristics 1 to 7 appear in most cases: 1. Weight: low birth weight in term infant. 2. Ears: low set and/or abnormal shape. 3. Micrognathia and microstomia. 4. Mental retardation. 5. Hands. a. Clenched hand with flexed fingers. b. Flexion contraction of the two middle digits. c. Unfolded thumb. 6. Cardiac: usually ventricular septal defect with patent ductal arteriosus. 7. Feet: rocker bottom.Characteristics 8 to 14 may also appear: 8. Eyes: ptosis of one or both eyelids. 9. Syndactyly. 10. Head: abnormally prominent occiput. 11. Genitourinary defects. 12. Hernias, especially umbilical. 13. Simian crease appears in 25%. 14. Arches on seven or more fingers in 80% of cases. D. Complications and outcome. 1. Mortality rate: 30% die within 2 months of birth, usually of heart failure. 2. Survival: 10% survive past the first year with severe developmental delay. E. Care management. 1. No treatment beyond supportive care. 2. Gavage/gastric tube feedings as needed for poor feeding. 3. Oxygen as needed for respiratory distress. 4. Parental support. A. Etiology: unknown; may be related to older maternal age. B. Incidence: 1 in 15,000 births. C. Clinical presentation. 2. Ears: malformed. 3. Hands: flexion deformities of hand, fingers, and wrist (postaxial polydactyly). 4. Cardiac: usually ventricular septal defect, patent ductus arteriosus, or rotational anomalies such as dextroposition. 5. Feet: rocker bottom. 6. Eyes: microphthalmos, colobomas of iris, cataracts. 7. Nose: broad and flattened, cleft lip and palate (not always). 8. Umbilicus: hernia, omphalocele. 9. Genitalia: a. Female: bicornuate or septate uterus. b. Male: cryptorchidism, small scrotum and anterior placement. 10. Kidneys: polycystic. 11. Skin: cutaneous hemangiomas, cutis aplasia. 12. Brain: gross defects, grand mal seizures, myoclonic jerks. 13. Hematologic abnormalities, such as increased frequency of nuclear projections in neutrophils and/or persistence of embryonic and/or fetal type of hemoglobin. D. Complications and outcome. 1. Mortality rate: 44% die within the first month. 2. Survival: 18% survive the first year. 3. Severe mental retardation. E. Care management. 1. No treatment beyond supportive care. 2. Parental support.
Genetics
From Bench to Bedside
BASIC GENETICS
Terminology
Dominance and Recessiveness
Autosomal Disorders
X-Linked Disorders
Mitochondrial Disorders
CHROMOSOMAL DEFECTS
Abnormal Number
Abnormal Structure
PRENATAL DIAGNOSIS
Indications and Advantages of Prenatal Diagnosis
Prenatal Tests
Triple and Quad Screen Tests
Ultrasonography
Amniocentesis (“Amnio”)
Chorionic Villus Sampling
Percutaneous Umbilical Blood Sampling
POSTNATAL TESTING
HUMAN GENOME PROJECT
GENETIC COUNSELING
NEWBORN CARE
Diagnosis
History
Examination and Care
Examples of Specific Disorders (for More Specific Disorders, See Chapter 35)
VATER Association
VACTERL Association
Common Trisomies
Trisomy 21 (Down Syndrome)
Trisomy 18
Trisomy 13
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