Spontaneous Chromosomal Deletion
• Prenatal diagnosis
• Ultrasound screening
• Interstitial deletion
• Cytogenetic and genome analysis
• Genetic counseling
• Pregnancy management options
Major Phenotypic Features
• Age at onset: Prenatal
• Intrauterine growth restriction
• Increased nuchal fold
• Dysmorphic facies
History and Physical Findings
A.G. is a 26-year-old gravida 2, para 1 white woman referred for ultrasonography for detailed examination of fetal anatomy. A.G. denied any medication, drug, or alcohol exposure in the pregnancy, and both parents were in good health. The biometric parameters from the fetal anatomy study suggested a 17.5-week fetus. On the basis of first-trimester ultrasound dating and the date of the patient's last menstrual period, however, the fetus should have been at approximately 21 weeks of gestation. This discrepancy suggested symmetrical fetal intrauterine growth restriction. Further evaluation also revealed increased nuchal fold measurements of 6.1 to 7.3 mm. The couple was counseled regarding the increased risk for fetal aneuploidy, and amniocentesis was elected. The chromosome results revealed an interstitial chromosome 4p deletion, with karyotype 46,XX,del(4)(p15.1p15.32). Parental chromosomes were normal. After extensive genetic counseling, the couple decided to terminate the pregnancy. The autopsy revealed a 19-week fetus by size (22.5 weeks by dates) with bilateral epicanthal folds, low-set and posteriorly rotated ears, prominent nasal bridge, and micrognathia. Redundant posterior nuchal skin was also noted.
Disease Etiology and Incidence
Intrauterine growth restriction (IUGR) is diagnosed when a fetus or neonate is less than 10th percentile for weight (<2500 g for a neonate born at term in the United States) (Fig. C-27). A newborn with IUGR should be distinguished from a newborn who is small for gestational age (SGA) who is also below the 10th percentile in size but is small for physiological reasons, such as the size of the parents. Approximately 7% of pregnancies result in a fetus who is SGA, of which approximately 1 in 8 is truly IUGR.
FIGURE C-27 Intrauterine growth curve for a fetus with trisomy 18 (black line), superimposed on a standard intrauterine and postnatal growth chart averaged for both sexes over the U.S. population (shown in blue). The aneuploid fetus's growth curve begins at the 30th percentile at 27 weeks of gestation but then cuts across percentile lines, as shown, culminating in birth at 38 weeks with fetal weight just below the third percentile. Fetal weight during pregnancy is estimated by a formula that combines ultrasound measurements of the distance between the parietal bones of the fetal skull (biparietal diameter), head circumference, abdominal circumference, and femur length. See Sources & Acknowledgments.
IUGR may result from uteroplacental insufficiency, exposure to drugs or alcohol, congenital infections, or intrinsic genetic limitations of growth potential. Fetuses with growth restriction due to nutritional compromise tend to have less retardation of head growth compared to the rest of the body. Several chromosomal disorders are associated with IUGR, and a finding of early or symmetrical IUGR increases the likelihood that a fetus is affected with a chromosomal abnormality such as trisomy 18, triploidy, or maternal uniparental disomy for chromosome 7 or 14. Nuchal fold measurements of more than 3 mm in the first trimester (11 to 14 weeks) and of 6 mm or more in the second trimester are considered increased and are associated with a greater risk for Down syndrome. Approximately one in seven fetuses with a second-trimester nuchal thickening will have Down syndrome. The ultrasound findings in A.G.'s fetus increased the suspicion of aneuploidy and led to the identification of the small interstitial deletion in 4p, which is the likely explanation for the fetal abnormalities.
The etiology and incidence of such a rare deletion are not entirely understood, especially in light of the normal parental chromosomes. Most de novo deletions are considered to originate at meiosis, but they may also arise during mitosis, before meiosis in gametogenesis, so that a parent is a gonadal mosaic. Gonadal mosaicism cannot be ruled out with any certainty by fibroblast or lymphoblast testing of the parents; consequently, prenatal testing should be offered in future pregnancies.
The deletion breakpoints on the short arm of chromosome 4 in 46,XX,del(4)(p15.1p15.32) flank a 14.5-Mb segment of DNA. Analysis of the human genome sequence in this region indicates that 47 known protein-coding genes exist within this deleted region; haploinsufficiency for one or more of these genes is the likely cause of the phenotype of this fetus. Chromosome microarray testing allows more precise definition of breakpoints in deletions or duplications than does prenatal karyotype, thus determining which genes are involved in the deleted area. This may add more precise prognostic information if the involvement of critical genes is in question.
Phenotype and Natural History
All pregnancies regardless of family, medical, or pregnancy history are at an approximate 3% to 5% risk for developmental disabilities or a birth defect in the infant. Although this couple was not at increased risk, the routine second-trimester ultrasound findings increased the suspicion of fetal aneuploidy. The finding of an interstitial deletion is likely to explain the ultrasound findings. Although this exact deletion had not been reported previously, many deletions of the short arm of chromosome 4 have been associated with birth defects. For example, Wolf-Hirschhorn syndrome is due to a microdeletion of 4p, resulting in both severe intellectual disabilities and physical anomalies. FISH analysis in this fetus revealed that the sequences for the Wolf-Hirschhorn critical region at 4p16.3 were present on both copies of chromosome 4 and that the deletion in this case was more proximal, in band p15. In this case, as with any substantial loss or gain of material on an autosome not previously reported in other patients, the outcome is likely to involve both physical and neurological impairment, the severity of which cannot be predicted.
No curative treatments are available for chromosome abnormalities. The overriding question for many couples regarding the outcome for their unborn child is whether the fetus is at risk for intellectual disability or a significant birth defect. In light of the already present ultrasound anomalies and the identified chromosomal abnormality, this fetus will have sequelae, the extent of which is not predictable. In such cases, the couple is counseled in detail about the limited information and the inability to conclude with any certainty about the expected outcome of the pregnancy. The options include continuation of the pregnancy with expectant management, with or without giving the neonate up for adoption, or termination of pregnancy.
Follow-up ultrasound evaluations can assess fetal growth and development. Long-term progressive IUGR alone suggests a poor prognosis for the fetus. By the late second trimester, the majority of cardiac lesions that would require intervention at birth can usually be identified. Consultation with neonatologists and maternal-fetal medicine specialists can provide information regarding what to expect at delivery and the types of postnatal evaluations that should be considered. There may be advantages to arranging for delivery in a tertiary facility that provides specialized neonatal intensive care and surgery.
Termination of the pregnancy is currently legal in the United States, but not always available. In the second trimester of pregnancy, this procedure can be performed by either dilation and evacuation or induction of labor (prostaglandin induction). The former is usually not performed in pregnancies of more than 24 weeks' gestation. Prostaglandin induction provides the couple with the option of an autopsy, but with a known serious chromosome anomaly, the information from an autopsy provides no additional information that would affect recurrence risk or prenatal testing options in a future pregnancy. The emotional and physical benefits and disadvantages of the two procedures should be outlined in detail before the patient's decision to terminate, should that option be chosen (see Chapter 17). In the majority of states in the U.S., pregnancy terminations are not covered by private health insurance, even when the indication is for a severe birth defect diagnosed prenatally. The costs can be in excess of thousands of dollars, and the financial burden of this procedure may affect decision making in some individuals.
Finally, the parents can be offered the option of giving the neonate up for adoption if they decide that termination is either not an option or unaffordable, or because the anomalies were identified too late in the pregnancy to allow termination.
De novo deletions have a low recurrence risk, due to the chance of undetectable gonadal mosaicism in either parent. Prenatal testing, such as chorionic villus sampling or amniocentesis, is available for future pregnancies, although the risk for miscarriage from these procedures may be comparable to the actual empirical risk for a recurrence.
Questions for Small Group Discussion
1. What is the difference between the terms small for gestational age (SGA) and intrauterine growth restriction (IUGR)?
2. What would be the advantages and disadvantages of performing amniocentesis for karyotype at 24 weeks of gestation in a pregnancy thought to have IUGR, even if the societal regulations and family situation preclude a pregnancy termination if the amniocentesis demonstrates a chromosomal abnormality?
Bianchi D, Crombleholme T, D’Alton M, et al. Fetology: diagnosis and management of the fetal patient. ed 2. McGraw Hill: New York; 2010.
Gardner RJM, Sutherland GR, Shaffer LG. Chromosome abnormalities and genetic counseling. ed 4. Oxford University Press: Oxford, England; 2012.
South ST, Corson VL, McMichael JL, et al. Prenatal detection of an interstitial deletion in 4p15 in a fetus with an increased nuchal skin fold measurement. Fetal Diagn Ther. 2005;20:58–63.