Genetics

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Chapter 11

Genetics

Anencephaly and spina bifida, occurring with a prevalence of about 0.5 to 2 of 1000 live births, and congenital heart disease, with a prevalence of approximately 1%, are the most common. 1

This point has been argued for years. A single umbilical artery is a rare phenomenon. In one study of nearly 35,000 infants, examination of the placenta showed that only 112 (0.32%) had a single umbilical artery. All 112 underwent renal ultrasonography, and 17% had abnormalities (45% of which persisted). A more recent study demonstrated that left umbilical arteries tend to be absent more often than right umbilical arteries when only a single artery is present. In addition, there was a high incidence of associated congenital malformations in nearly 25% of the infants diagnosed prenatally with a single umbilical artery. Because of the rarity of the condition and the increased association of abnormalities, patients with single umbilical arteries probably should receive a screening renal ultrasound. 2

There is some variation in the sensitivity of the screening methods, depending on the tests used and the timing of the screening. Maternal serum alpha-fetoprotein (AFP), unconjugated estriol (uE3), and human chorionic gonadotropin (hCG) make up the “triple test” and with the addition of inhibin A makes up the “quadruple screen.” Maternal serum pregnancy–associated plasma protein (PAPP)-A and free beta-hCG are used at 11 to 13 weeks along with nuchal translucency followed by maternal serum AFP, hCG, uE3, and inhibin at 15 to 18 weeks of gestation to provide an integrated first- and second-trimester screen with a sensitivity of 91% and 4.5% false-positive results. Absent fetal nasal bone is another marker under investigation for Down syndrome screening.

Recently a new test has been developed that analyzes circulating cell-free DNA extracted from a maternal blood sample. The test detects an increased representation of chromosome 21 material, which is associated with trisomy 21. The Down syndrome detection rate was 98.6% with a false-positive rate of 0.20% This test is not recommended for population-based screening but may be used for women who screen positive on serum screening before proceeding to an invasive diagnostic test. 34

None. A positive triple screen is a screening test, not a diagnostic test. If the infant looks healthy without features of Down syndrome or other anomalies, no further testing is necessary. Chromosome tests do not need to be performed on a normal-appearing infant just because the triple test result was abnormal.

6. How would you evaluate a newborn with Down syndrome to ensure you are discharging a healthy infant? What serious abnormalities are likely?

image KEY POINTS: COMMON CAUSES OF BIRTH DEFECTS

7. A macrosomic infant is born with an omphalocele and large tongue. What would you anticipate monitoring closely in this baby, and why?

This baby may have Beckwith–Wiedemann syndrome and may be at risk for hypoglycemia. Other signs of Beckwith–Wiedemann syndrome include grooves or pits on the ear lobes, hemihypertrophy, and visceromegaly ( Fig. 11-1). These children are at risk for Wilms tumor and hepatoblastoma and should be monitored with an abdominal ultrasound and AFP testing every 4 months for the first 6 years of life.

Yes, in vitro fertilization is associated with an increased risk of Beckwith–Wiedemann syndrome and other rare imprinting disorders.

Omphalocele:

Gastroschisis:

Congenital diaphragmatic hernia is an associated inherited condition in the following syndromes:

11. A female infant is born with the following features: puffiness of the dorsum of the hands and feet, excessive skin at the nape of the neck with a low posterior hairline, and a broad chest and widely spaced nipples. What is the differential diagnosis?

12. How would you work up the baby in Question 11?

image Chromosome study on peripheral blood (G-banding)

image Genetic testing for Noonan syndrome if chromosomes are normal

image Cardiac evaluation, including echocardiogram

image Renal ultrasound

image Referral for genetic counseling and early intervention

image KEY POINTS: PRINCIPLES OF BIRTH DEFECTS

13. How do you perform genetic testing for Noonan syndrome?

Noonan syndrome overlaps with LEOPARD, cardiofaciocutaneous, and Costello syndromes. All are autosomal dominant disorders typically caused by gain-of-function mutations in genes encoding signaling molecules of the RAS/MAPK pathway (PTPN11, RAF1, SOS1, KRAS, BRAF, MAP2K1, MAP2K2, HRAS, NRAS, CBL, SHOC2). Genetic testing can be performed on a blood sample and ideally should include testing for this panel of genes to maximize the sensitivity to make the diagnosis. Identification of a specific mutation will provide some prognostic information about risk of arrhythmias, cardiomyopathy, and learning or intellectual disabilities. Genetic testing will also provide the family with important information about the risk of recurrence within the family. Noonan syndrome is autosomal dominantly inherited, but for cases diagnosed prenatally or neonatally, many result from de novo mutations.

Yes, the panel of 11 genes can be tested prenatally for Noonan syndrome using either a chorionic villus or amniocentesis sample. The most common ultrasound findings are increased nuchal translucency or cystic hygroma.

Fetal growth restriction is the failure of a fetus to achieve its growth potential. In practice, measures of size relative to the population mean for gestational age and sex are used. Fetal growth retardation is variably defined as an infant who is either below the 10th percentile or less than two standard deviations (SDs) below the population mean for that gestational age and sex.

16. Intrauterine growth restriction (IUGR) has many causes. What approach would you use to evaluate a newborn with IUGR?

image Establish whether the growth restriction is proportionate or disproportionate.

image Perform a detailed physical examination for anomalies or dysmorphic features.

image If dysmorphic or multiple anomalies are present, chromosome studies are indicated.

image Take a detailed pregnancy history to look for teratogenic exposures, smoking, infection history, or maternal illness (e.g., hypertension and preeclampsia).

image Viral studies and antibody titers should be ordered as indicated.

image Uncontrolled maternal phenylketonuria can be associated with IUGR and microcephaly.

image An infant with disproportionate IUGR should be worked up for skeletal dysplasia or metabolic bone disease.

image Proportionate IUGR may be associated with many dysmorphic syndromes that may be recognized by a geneticist.

image Placental examination for size and infarction and placental genetic studies should be performed for confined placental mosaicism and uniparental disomy (UPD).

17. What is confined placental mosaicism?

The abnormal cell line in this condition is “confined” either to the cytotrophoblast or chorionic stroma cells of the placenta and is not present in the fetus itself. This situation may be discovered when an abnormal karyotype results from chorionic villous sampling (CVS) reflecting the placenta, but the fetus appears to be healthy and amniocentesis is normal. The diagnosis of confined placental mosaicism postnatally is usually made retrospectively by follow-up studies on the infant or fetus, placenta, and membranes. Confined placental mosaicism may be associated with growth impairment in chromosomally normal fetuses. It may increase the risk of a spontaneous abortion. Overall, there appears to be a low risk of adverse pregnancy outcome with confined placental mosaicism.

UPD occurs when both members of a chromosome pair are derived solely from one parent in a diploid offspring. Many cases of UPD are the result of resolved trisomies in which the embryo was initially trisomic but lost one of the extra chromosomes and ended up with two chromosomes from the same parent. The disomy may be two copies of the same chromosome (i.e., isodisomy) or one copy of each of the given parent’s chromosomes (i.e., heterodisomy).

19. What conditions are associated with UPD?

20. What conditions are commonly diagnosed by fluorescent in situ hybridization (FISH)?

21. Can microdeletion syndromes such as DiGeorge syndrome be detected by a routine karyotype?

Whereas large deletions (greater than 5 megabases in size) are sometimes detectable on a karyotype, submicroscopic deletions cannot be visualized even on high-resolution chromosome banding. These deletions can be detected by FISH. In this technique a DNA probe specific for the chromosomal region of interest is hybridized to the chromosomes. A fluorescent signal is attached to the probe so that the number of copies of the DNA corresponding to the probe can be determined for each cell. Normally, two copies of each region, one on each chromosome, should be present. If a deletion has occurred, only one of the copies will be seen. FISH is not always reliable for detecting duplications, however. This technique has aided in the diagnosis of microdeletion syndromes that were once difficult to detect because of their small size.

An example of the use of FISH is for rapid prenatal diagnosis of trisomies on amniotic fluid or chorionic villi, using interphase cells from cultured specimens and probes for the most common chromosomal abnormalities (13, 18, 21, X, and Y). Although interphase FISH for prenatal diagnosis has low false-positive and false-negative rates, it is considered investigational and is used only in conjunction with standard cytogenetic analysis. FISH is also useful in diagnosing the microdeletion genetic syndromes noted in Question 20.

image KEY POINTS: CHROMOSOMAL DEFECTS

1. The risk of aneuploidy increases with advanced maternal age; however, most aneuploid births are to mothers who are not of advanced maternal age. The majority of trisomies are a result of maternal meiotic errors; however, almost half of Klinefelter cases are caused by errors in paternal meiosis.

2. Screening for Down syndrome with a combination of noninvasive ultrasound markers of nuchal translucency and maternal serum markers allows for greater than 95% sensitivity in detecting Down syndrome.

3. Microdeletions are too small to be resolved by a karyotype and require fluorescence in situ hybridization. The majority are de novo and not inherited. They are associated with a variety of clinical syndromes such as DiGeorge syndrome, Williams syndrome, Angelman syndrome, Miller–Dieker syndrome, Smith–Magenis syndrome, and Kallmann syndrome.

4. Balanced translocations have the total correct amount of DNA. If the balanced translocation is inherited, the phenotype in the child is predicted to be that of the balanced translocation carrier parent. If the translocation is de novo, there is an approximately 15% chance it will be associated with a phenotypic consequence such as a birth defect, cognitive impairment, or medical problem.

5. UPD means that for one set of chromosomes, both chromosomes were inherited from the same parent. If genes on that chromosome are imprinted, this can produce specific clinical symptoms, such as Prader–Willi syndrome. UPD cannot be detected by a standard karyotype but can be detected with other molecular genetic techniques.

This is analogous to series of thousands of FISH probe panels that cover all known microdeletion and microduplication syndromes and can detect deletions or duplications of at least 1 megabase on all the chromosomes to detect genomic imbalances. The resolution of the chromosome microarray varies by laboratory, and higher and lower density arrays are available depending on the needs of the clinical situation. All fetuses with major anomalies or IUGR should be offered this test. Patients with dysmorphic features, major congenital anomalies, developmental delay, intellectual disability, seizures, and failure to thrive should have this test.

Chromosome microarray is now considered the first line test to evaluate chromosomes. The only anomalies missed by a chromosome microarray are balanced translocations and low levels of mosaicism, but the prevalence of these types of chromosomal disorders is low. 5

Anophthalmia is the medical term used to describe the absence of the globe and ocular tissue from the orbit. Anophthalmia and microphthalmia are often used interchangeably because, in most cases, the magnetic resonance imaging (MRI) or computed tomography (CT) scan shows some remnants of either the globe or surrounding tissue. Anophthalmia may be unilateral or bilateral and is often associated with other anomalies. There are many causes of anophthalmia including single gene mutations, syndromes, chromosome abnormalities, and teratogenic exposures. Anophthalmia is rare, with an incidence of about 1 in 10,000.

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