Genetic Issues Presenting in the Nursery
Carlos A. Bacino
KEY POINTS
Approximately 1 in 20 newborns have a major birth defect.
Evaluation includes a comprehensive medical/family history and physical examination.
Testing should be targeted to a suspected etiology.
I. GENERAL PRINCIPLES
A. Approximately 4% to 5% of newborns have a major birth defect and require genetic evaluation. These birth defects or malformations can be sporadic or associated with other anomalies. Some children may have physical features consistent with a well-known syndrome, whereas others may have sporadic anomalies detected prenatally or postnatally. Other neonatal presentations include acidosis that occurs with some inborn errors of metabolism (IEM), unexplained seizures, extreme hypotonia, or feeding difficulties. Infants with ambiguous genitalia require a multidisciplinary evaluation involving clinicians from genetics, endocrinology, urology, pediatrics or neonatology, and psychology. A thorough clinical evaluation requires a detailed prenatal history, a family history, and a comprehensive clinical exam, often including anthropometric measurements.
B. Congenital anomalies are considered major or minor.
1. Major malformations are structural abnormalities that have medical and cosmetic consequence. They may require surgical intervention. Examples include cleft palate and congenital heart disease such as tetralogy of Fallot.
2. Minor malformations are anomalies with no medical or cosmetic significance. A single transverse palmar crease is an example, although most minor abnormalities are limited to the head and neck region. Minor anomalies may aid in the diagnosis or recognition of a specific syndrome. Infants with three or more minor malformations are at high risk for having a major malformation (20% to 25%) and/or a syndrome.
C. Major and minor malformations are often part of patterns.
1. A syndrome consists of a group of anomalies that are associated due to single or similar etiologies, with known or unknown cause, such as Down syndrome due to trisomy 21.
2. Associations are clusters of malformations that occur together more frequently than occur sporadically, such as VACTERL association (vertebral, anal, cardiac, tracheoesophageal fistula, renal, and limb—radial ray defects) where at least three anomalies are required for the diagnosis.
3. A developmental field defect consists of a group of anomalies resulting from defective development of a related group of cells (developmental field). In this case, the involved embryonic regions are usually spatially related but may not be contiguous in the infant. Holoprosencephaly affecting the forebrain and face is an example and secondary to an abnormality in a group of cells that form the rostral aspect of the prechordal mesoderm that will ultimately induce development of the forebrain and midface.
4. Disruptions are extrinsic events that occur during normal development. These events can compromise the fetal circulation and result in a major birth defect. An example of a disruption is amniotic bands that may result in amputation of digits or limbs.
5. Deformations can occur when physical forces act on previously formed structures. Examples of deformations include uterine crowding or oligohydramnios that results in plagiocephaly or clubfeet.
II. INCIDENCE. The Centers for Disease Control and Prevention (CDC) monitors rates of birth defects in the United States (http://www.cdc.gov/ncbddd/birthdefects/data.html). Approximately 1 of 33 children has a major birth defect. Infants with birth defects account for 20% of infant deaths.
III. ETIOLOGY. The etiology of approximately 50% of birth defects is unknown. Of the remainder, etiology is attributed as follows: 6% to 10% chromosomal, 3% to 7.5% single-gene Mendelian disorders, 20% to 30% multifactorial, and 4% to 5% environmental exposures. The development of more sensitive molecular technology is likely to establish etiology in more cases.
IV. APPROACH TO THE INFANT WITH BIRTH DEFECTS
A. A comprehensive history is an important step in evaluating an infant with a birth defect.
1. Prenatal history should include the following:
a. Chronic maternal illnesses including diabetes (insulin- and non-insulindependent), seizures, hypertension, myotonic dystrophy, phenylketonuria, Graves disease (see Table 10.1 for prenatal exposures and effects).
b. Drug exposures should include prescribed drugs, such as antihypertensives (angiotensin-converting enzyme inhibitors), seizure medications, antineoplastic agents (methotrexate), and illicit drugs (e.g., cocaine).
Other drugs that may result in birth defects include misoprostol (to induce abortions). Timing of the exposure is important. Teratogenic agents tend to have their maximum effect during the embryonal period, from the beginning of the fourth to the end of the seventh week postfertilization, with the exception of severe forms of holoprosencephaly when exposure may occur around or before 23 days (see Appendix B).
Other drugs that may result in birth defects include misoprostol (to induce abortions). Timing of the exposure is important. Teratogenic agents tend to have their maximum effect during the embryonal period, from the beginning of the fourth to the end of the seventh week postfertilization, with the exception of severe forms of holoprosencephaly when exposure may occur around or before 23 days (see Appendix B).
Table 10.1. Well-Recognized Human Teratogens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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c. Infections and immunizations
d. Social history
e. Other exposures may include alcohol; physical agents such as x-rays, high temperature; chemical agents; tobacco (see Table 10.1).
f. Nutritional status
g. Fertility issues and use of reproductive assistance (e.g. history of multiple miscarriages, in vitro fertilization [IVF] or medications to stimulate ovulation). Genetic disorders such as Beckwith-Wiedemann syndrome, Silver-Russell syndrome, and Angelman syndrome that can be caused by imprinting defects (epigenetic mutations) have been seen in children conceived by assisted reproductive technology using intracytoplasmic sperm injection (ICSI).
h. Multiple gestations (see Chapter 11)
i. Results of prenatal studies should be obtained including ultrasonographic and magnetic resonance imaging (MRI) and chromosome or
microarray studies done on samples obtained by amniocentesis, chorionic villi sampling (CVS), or percutaneous umbilical blood sampling.
microarray studies done on samples obtained by amniocentesis, chorionic villi sampling (CVS), or percutaneous umbilical blood sampling.
j. Results should be obtained from first- and second-trimester screening including triple and quad screens. First-trimester screening combines the use of nuchal translucency with serum levels of pregnancy-associated plasma protein A (PAPP-A) and human chorionic gonadotropin (hCG) measured as free beta subunit (β-hCG) or total hCG. The secondtrimester screen includes alpha-fetoprotein (AFP), unconjugated estriol (uE3), free β-hCG for the triple screen, plus inhibin A, as part of the quad screen. A low maternal serum alpha-fetoprotein (MSAFP) level can be seen in trisomies 21, 18, and 13. A high MSAFP may be a sign of multiple gestation, open neural tube defect, abdominal wall defect, impending fetal death, congenital nephrosis, or epidermolysis bullosa. A high hCG can be seen with trisomy 21, whereas low hCG may occur with trisomies 18 and 13.
k. Noninvasive prenatal testing (NIPT) is slowly replacing the first- and second-trimester screens. This technique consists of the analysis of cellfree fetal DNA present in maternal serum. Many companies provide this analysis and mostly target the presence of common trisomies such as trisomy 21 (Down syndrome, sensitivity 99.3%) and trisomy 18 (sensitivity 97.4%). Sensitivity is lower for trisomy 13 (91.4%) and sex chromosome (91%). NIPT is used in high-risk situations such as advanced maternal age and abnormal ultrasound examinations. For low-risk presentations, conventional first- and or second-trimester screens are preferred. The American College of Obstetricians and Gynecologists recommends conventional screening methods as the most appropriate choice for first-line screening for most women in the general obstetric population.
l. Newer forms of NIPT include common microdeletions, e.g., 22q11.2 microdeletions (DiGeorge/velocardiofacial syndrome [VCFS]) and Wolf-Hirschhorn deletion.
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