TeraBody5-26-Chaps1-30 9/22/05 1:43 PM Page 1 What are Common Birth Defects in Humans, and How are They Diagnosed? CHAPTER 1 A major malformation is defined as a structural abnormali- ty that is either lethal, requires treatment (medical or surgical), or is of cosmetic importance. These abnormalities occur with similar frequency in all species studied, including humans, mice, rats, dogs, cats, pigs, cows, and horses. Structural abnormalities are a major factor in the survival of an embryo or fetus; in every species, the frequency of malfor- mations is highest in pregnancies that result in miscarriages or still- births. About two percent of n e w- born infants are identified as having a major malformation at birth. Examples of common major malformations include: •Heart defects, such as a ventricular septal defect •Down Syndrome (Trisomy 21, characterized by mental retardation, a sloping forehead, low-set ears, a flat nose, and short, broad hands) •Spina bifida (defective development of the spinal cord and a failure of the overlying skin and vertebrae to close properly, producing weakness or paralysis below the defect) •Polydactyly (an extra finger, usually next to the fifth finger; occasionally there is an extra thumb) •Fetal alcohol syndrome (a growth deficient infant with a distinctive pattern of facial features) Newborn infants are examined at the time of delivery by the birth attendant, and then more thoroughly by the baby’s health care provider a few hours later. If a fetal abnor- mality was detected during pregnancy, by prenatal screening or ultrasound, a pediatrician may be present in the delivery room to assess whether the infant requires intensive care. The newborn examination includes looking for abnormal facial features, an abnor- mally large or small head, extra fingers, webbing between fingers, genital abnormalities and a club foot. Examining the abdomen and listening to the heart may detect other defects. TeraBody5-26-Chaps1-30 9/22/05 1:43 PM Page 2 2 Teratology Primer Common Birth Defects 3 Despite the routine examination of babies, not all birth defects are detected at birth. Kidney • Multifactorial inheritance abnormalities, heart defects, hip dysplasia and brain abnormalities may not be detected until Both genetic and non-genetic factors contribute to many birth defects. Genetic factors may months or years later. If several malformations are identified, chromosome analysis is done affect the occurrence of spina bifida, but the intake of folic acid by the mother at the time of on white blood cells and a geneticist can be consulted. conception is also very important. The geneticist examines the infant and interviews the parents to review the pregnan- cy and family history to find out, for example, whether other relatives have similar malforma- • Environmental causes of birth defects include teratogenic exposures to physical, tions, or whether the mother had a chronic disease, such as diabetes, or exposure to a drug chemical or biological agents and conditions. For example, smoking cigarettes or using that could have affected the infant. The geneticist determines whether the baby has a recog- cocaine can affect the fetus and cause harm. Drinking an excessive amount of alcohol caus- nized pattern of problems and advises the parents about probable causes and the options for es abnormal embryofetal development and affects 1 in every 500 to 1,000 humans. treatment. Additional tests, such as DNA studies, may be ordered. • Twinning Recognized causes of major malformations include: The frequency of malformations is higher in identical than in non-identical twins. In fact, identical twinning, which is a splitting apart of a zygote or early embryo, can itself be consid- • A Dominant Gene ered a developmental abnormality. An infant with a skeletal dysplasia, such as achondroplasia, could have inherited the dominant gene that causes this condition from an affected mother or father. The infant could also be Education can help prevent some major malformations. If all women of childbearing affected as the result of a spontaneous mutation, in which case the infant would be the first age took before becoming pregnant a daily vitamin containing at least 0.4 mg folic acid, the affected member of the family. rate of spina bifida and some other types of birth defects would decrease. Diabetics with well- controlled glucose levels before conception have half the risk of having a malformed child • A Recessive Gene compared to diabetics with poorly controlled blood sugars. Women who plan their pregnan- In infantile polycystic kidney disease, a child is affected because both parents carry the same cies can stop smoking cigarettes and drinking alcohol before they conceive. Women who take rare recessive gene. Parents who carry the gene are unaffected, but their children have a one anti-seizure medications can discuss changing to a drug that poses the least risk during pregnancy. in four chance of being affected. The web site: www.genetests.org can be used to identify laboratories which provide analyses for gene mutations that have been identified for about 10% of the recognized disor- ders due to either dominant or recessive genes. Disorders due to these genes are listed in the website Mendelian Inheritance in Man. • Chromosome abnormalities Having an extra chromosome causes specific syndromes. The presence of an extra number Suggested Reading 21 chromosome causes Down Syndrome, also called trisomy 21. An extra number 18 chro- mosome (trisomy 18) or number 13 chromosome (trisomy 13) are less common than Down Jones KL. Smith’s Recognizable Patterns of Human Malformation, Fifth Edition. W.B. syndrome; all of these syndromes cause mental retardation but each syndrome is associated Saunders Company: Philadelphia, 1997. with a different set of malformations. Other chromosome abnormalities include the presence of an extra X chromosome (47,XXX) or the absence of one X (45, X: Turner Syndrome), Nelson K, Holmes LB. Malformations due to spontaneous mutations in newborn infants which is associated with a webbed neck and, in newborns, swelling of the hands and feet. N Engl J Med 1989; 320:19-23. Adults with Turner’s syndrome never develop breasts or other secondary sexual characteristics. Schinzel AA, Smith DW, Miller JR. Monozygotic twinning and structural defects. J Pediatr In the 1990s it became possible to detect a missing chunk of chromosome material 1979; 95:921-30. in cases where the number of chromosomes was normal. These deletions are the basis for dis- orders like the Prader-Willi Syndrome (deletion in chromosome 16, which is associated with Stevenson RE, Hall JG, Goodman RM. Human Malformations and Related Anomalies, short stature, small hands and feet, obesity, overeating, and underdeveloped gonads) and Volume II. New York: Oxford University Press, 1993. Williams Syndrome (deletion in chromosome 7), which is associated with an elf-like face, mental retardation, short stature, and cardiac abnormalities. Web site for Mendelian Inheritance in Man: www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM TeraBody5-26-Chaps1-30 9/22/05 1:43 PM Page 4 What Are Some Of The Important Events Occurring Important Events During Embryogenesis 5 During Embryogenesis That May Be Disrupted ly late in the fourth week of development, while the caudal neuropore closes a few days later. By A Teratogen? Interference with neurulation causes such neural tube defects as anencephaly (absence of portions of the brain and overlying skull), exencephaly (protrusion of brain tissue through a defect in the skull), and spina bifida (split spine: failure of vertebrae to close). The sensory and autonomic components of the peripheral nervous system derive from two progenitor cell populations. The first is called neural crest because it originates at the margin of the neuroectoderm. Neural crest cells leave the margins of the folding neuroec- CHAPTER 2 toderm around the time the neural tube is closing. They migrate throughout the embryo and give rise to most of the nerves outside the brain and spinal cord. The second progenitor cell Most major structural mal- population derives from the cranial placodes (thickenings in the surface ectoderm that are formations triggered by environ- associated with the future nose and ear as well as other craniofacial regions). Some of the mental exposure to teratogens are cranial sensory neurons develop from these cranial placodes. initiated during the embryonic Neural crest cells contribute importantly to a number of other embryonic compo- period, which, in the human, nents, as well. These include the facial skeleton and connective tissue. Therefore, it is easy e x t e n d s between the third and to see that the presence of a particular teratogen at a specific “sensitive” time might dramat- eighth week of gestation. This crit- ically affect a variety of forming structures. For example: should those neural crest cells ical six-week period sees the con- entering the forming facial region be delayed, disrupted in some fashion, or even killed, the ceptus change from a relatively face might develop devoid of some or most skeletal and connective tissue elements as well as simple bilayered disk of cells into a exhibiting abnormalities in its innervation. distinctly human fetus of mar- Teratologists often single out “critical events”, which are key developmental steps velous intricacy. The speed and that are completed by a particular developmental stage. Such events include gastrulation, complexity of this extraordinary neural tube closure, septation of the heart into separate chambers, and fusion of the second- m e t a m o r p h o s i s makes the fact ary palatal shelves. Although an embryonic organ may be damaged by an environmental insult after its development is essentially complete, damage from such insults usually occurs that the process normally proceeds Photos courtesy of Kathleen Sulik without incident the more remark- earlier in the morphogenesis of that organ.