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.

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:

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.

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).

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.

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.

CVS is the aspiration of chorionic villi through a transcervical catheter or transabdominal needle using ultrasound guidance. The main advantage of CVS is that it can be done between 10 and 12 weeks of gestation compared with the usual 16-week timing for amniocentesis. This permits the termination of pregnancy at a significantly earlier date in the event of major chromosomal or genetic anomalies. CVS does not permit analysis of the amniotic fluid AFP levels, so screening for neural tube defects must be performed with maternal serum AFP and ultrasound.

See Table 11-1.

A single transverse palmar crease is present in 4% of normal newborns. Bilateral palmar creases are found in 1%. These features occur twice as commonly in males than in females. However, 50% to 55% of newborn infants with Down syndrome have a single transverse crease. Because Down syndrome occurs in 1 of every 800 live births, the chance that a newborn with a simian crease has Down syndrome is only 1 in 60.

The IQ range is generally 35 to 65, with a mean reported IQ of 54. Occasionally the IQ may be higher. Intelligence deteriorates in adulthood, with clinical and pathologic findings consistent with advanced Alzheimer disease. Autopsy results from the brains of deceased adults with Down syndrome reveal both neurofibrillary tangles and senile plaques, as found in Alzheimer disease. By age 40 the mean IQ is 24. Children with Down syndrome are generally affectionate and docile. They tend toward mimicry and are noted usually to enjoy music, having a good sense of rhythm. However, 13% have serious emotional problems, and their coordination is usually poor.

There is a well-known association between advanced maternal age and trisomies (including XXY; XXX; and trisomies 13, 18, and 21). Most cases of Down syndrome involve nondisjunction at meiosis I in the mother. This may be related to the lengthy stage of meiotic arrest between oocyte development in the fetus and ovulation, which may occur as many as 40 years later ( Table 11-2). With the advent of multiple noninvasive methods to screen for aneuploidies, invasive testing is driven more by results on the screening tests rather than maternal age alone.

Only 34% of babies are born to mothers older than 35 years of age. Although their individual risk is higher, women in this age bracket account for only 5% of all pregnancies in the United States. ⁶

Of all cases of Down syndrome, 3.3% are caused by unbalanced Robertsonian translocations in which a third copy of chromosome 21 is present, attached to an acrocentric chromosome. The chance of translocation Down syndrome is two to three times greater in children of younger mothers (6% to 8% of mothers younger than 30). One of three infants with translocation Down syndrome will have a parent with a Robertsonian translocation. Two thirds of the time, translocation Down syndrome occurs as a de novo event in the infant.

The answer depends on the chromosome complement of the parents. In chromosomally normal women under the age of 40, the recurrence risk for Down syndrome after having had one fetus or baby with Down syndrome is 1% (assuming the father’s chromosomes are also normal). When the mother is older than age 40, the risk of having a child with Down syndrome increases, primarily as a function of her age. If the mother carries a translocation, the recurrence risk is 10% to 15%. If the father carries a translocation, the recurrence risk is 2% to 5%. One theory for this observed discrepancy between maternal and paternal rates of translocation Down syndrome is hindered motility of chromosomally abnormal sperm. If either parent is balanced and carries a 21;21 translocation, the recurrence risk for that parent is 100%.

Advanced paternal age is associated with de novo point mutations in all genes.

Neurofibromatosis. The estimated mutation rate for this disorder is 1 × 10⁴ per haploid genome. The clinical features are café-au-lait spots and axillary freckling in childhood, followed by development of neurofibromas in later years. Learning disabilities are common in NF1.

See Table 11-3.

Mitochondrial DNA abnormalities (e.g., many cases of ragged red fiber myopathies) are passed on from the mother because mitochondria are present in the cytoplasm of the egg and not the sperm. Transmission to male or female offspring is equally likely; however, expression can be variable within a family because of heteroplasmy with normal and abnormal mitochondria in differing proportions in different family members. ⁷

No. Many of the proteins found in the mitochondria are encoded within the nucleus. Those encoded within the nuclear genome are most commonly autosomal recessively inherited. They are still referred to as mitochondrial or oxidative phosphorylation defects and tend to result in more similar manifestations among affected family members.

Advanced paternal age is associated with new dominant mutations. The assumption is that the increased mutation rate is caused by accumulation of new mutations from many cell divisions in the spermatid as men age. The more cell divisions, the more likely that an error (mutation) will occur. The mutation rate in fathers older than 50 years is five times higher than the mutation rate in fathers younger than 20 years of age. New, common autosomal dominant mutations that are often the result of de novo mutations are achondroplasia, craniosynostosis, neurofibromatosis, and Marfan syndrome. ⁸

The most common is spinal muscular atrophy, an autosomal recessively inherited disease of the anterior motor neuron associated with decreased reflexes and progressive neuromuscular degeneration.

Hyperphagia, hypotonia, hypogonadism, and obesity. Up to 75% of patients have a paternal microdeletion on the long arm of chromosome 15. The gene or genes responsible for Prader–Willi syndrome are subject to parental imprinting. Imprinting is the process by which expression of a gene depends on whether it has been inherited from the mother or the father. The gene or genes associated with Prader–Willi syndrome are maternally imprinted or maternally silenced, meaning that loss of the paternal copy will result in the phenotype of Prader–Willi ( Fig. 11-3) because only the father’s copy is active. A closely related area of the long arm of chromosome 15 is maternally imprinted, and loss of the maternal copy leads to Angelman syndrome. Angelman syndrome is characterized by severe developmental delay; abnormal ataxic gait; seizures; inappropriate laughter; and jerking movements, especially of the arms. ⁹¹⁰¹¹

Twenty-one different skeletal dysplasia syndromes were classified at the International Nomenclature of Constitutional Diseases of Bone meeting as recognizable at birth. The most common is thanatophoric dwarfism, a lethal chondrodysplasia characterized by flattened, U-shaped vertebral bodies, telephone receiver–shaped femurs, macrocephaly, and redundant skin folds causing a puglike appearance. Thanatophoric means death-loving, and this is a lethal disorder. The incidence is 1 in 6400 births.

Achondroplasia is the most common viable skeletal dysplasia, occurring 1 in 26,000 live births. Its features are short stature (mean adult height, 4 feet 2 inches), macrocephaly, depressed nasal bridge, lordosis, and a trident hand. Some patients develop hydrocephalus because of a small foramen magnum. Radiographic findings include narrowing of the interpedicular distance as one proceeds caudally. Both achondroplasia and thanatophoric dysplasia are due to mutations in fibroblast growth factor receptor 3. In achondroplasia the mutation is in the transmembrane domain, whereas the mutation in thanatophoric dysplasia is either in the intracellular domain (type 2) or in the extracellular domain (type 1). ¹²

Cri du chat syndrome is due to a deletion of material from the short arm of chromosome 5 (i.e., 5p-) that causes many problems, including growth retardation, microcephaly, and severe mental retardation. Patients have a characteristic catlike cry during infancy from which the syndrome derives its name. In 85% of cases the deletion is a de novo event. In 15% it is caused by malsegregation resulting from a balanced parental translocation.

One of every 32 patients with isolated hemihypertrophy is at risk for developing Wilms tumor or hepatoblastoma. For this reason renal and abdominal ultrasound and AFP should be followed every 4 months until 6 years of age as screening for patients with hemihypertrophy.

Most newborns with hypoplastic left heart syndrome have this defect as an isolated abnormality, but several syndromes with which this congenital heart malformation is a component have been identified: Down syndrome, Turner syndrome, Smith–Lemli–Opitz syndrome, trisomy 13, trisomy 18, and Ivemark syndrome. Before extensive reconstructive surgery is attempted, it may be prudent to obtain a chromosome microarray analysis.

A fresh embryo or fetus implies a rapid expulsion after intrauterine or intrapartum death. These fetuses are usually without major anomalies and have normal karyotypes. Common causes of death are placental abruption, cord accidents, and infection. A macerated fetus indicates prolonged retention and is more likely to be associated with structural malformations or chromosomal anomalies.

In addition to an autopsy, other studies that should be considered include chromosomal analysis; skeletal radiographs; placental and cord histologic studies; titers for congenital infection; and, if hydropic, evaluation for a hemoglobinopathy (e.g., alpha-thalassemia) or possible metabolic storage disease. ¹³

Couples with recurrent pregnancy loss, defined as three or more losses, should be considered for the following evaluations:

It is particularly important to initiate these studies before pursuit of any in vitro fertilization approach because the pregnancy may be adversely affected again with a number of these problems.

Major malformations are unusual morphologic features that cause significant cosmetic, medical, or developmental consequences for the patient. Minor anomalies are features that do not have associated medical problems. Approximately 14% of newborns will have a minor malformation, whereas only about 2% to 3% will have a major malformation.

In early pregnancy (before 4 months), the majority of amniotic fluid is produced by transudation through the placental membranes and fetal skin. Later in pregnancy the bulk of amniotic fluid arises from fetal urination and fetal lung fluid production. At term the fetus swallows approximately 500 mL of amniotic fluid per day and urinates an equivalent amount. Fetal urine production increases rapidly from 3.5 mL/h at 25 weeks to 25 mL/h at term. Any malformation that leads to impaired urine production will cause oligohydramnios, including renal dysplasia, renal agenesis, and bladder outlet obstruction. When uteroplacental insufficiency occurs, the fetus is often faced with poor nutritive and volume support. The fetus becomes intravascularly depleted, leading to increased fluid conservation and decreased urine output, causing oligohydramnios. Oligohydramnios is often associated with IUGR.

The etiology of polyhydramnios may be broken down into maternal causes (30%), fetal causes (30%), and idiopathic causes (40%). Maternal disorders, such as diabetes, erythroblastosis fetalis, and preeclampsia, are often associated with excessive amniotic fluid. Fetal disorders that commonly predispose to polyhydramnios are central nervous system (CNS) anomalies (e.g., anencephaly, hydrocephaly, neurologic disorders), gastrointestinal disorders (e.g., tracheoesophageal fistula, duodenal atresia), fetal circulatory disorders, and multiple gestation. The etiology for polyhydramnios in fetuses with CNS and upper gastrointestinal tract anomalies is presumed to be impaired fetal swallowing ability.

Potter syndrome has come to be synonymous with fetal malformations caused by extreme oligohydramnios. A lack of amniotic fluid leads to fetal compression; a squashed, flat face; clubbing of the feet; pulmonary hypoplasia; and, commonly, breech presentation ( Fig. 11-4). Normal fetal lung development depends on in utero “breathing” and production of fetal lung fluid. In the absence of amniotic fluid, pulmonary hypoplasia occurs and is the cause of death for most fetuses with Potter syndrome. The underlying mechanism in Potter syndrome was initially reported to be renal agenesis or renal dysplasia. However, bladder outlet obstruction and prolonged premature rupture of the membranes may also cause this sequence. Some prefer that Potter syndrome be defined solely as renal agenesis.

Often, these children present in the neonatal period with severe respiratory distress beginning shortly after birth. Pneumothorax is common because high ventilatory pressures are often used in an attempt to initiate gas exchange. Survival rarely lasts longer than a few hours in the most severe cases.

Renal agenesis is thought to be a sporadic or multifactorial condition, although autosomal dominant inheritance with variable expression (i.e., unilateral renal agenesis in a parent) has also been postulated. For this reason obtaining a renal ultrasound on parents of a child with renal agenesis is advised. If the parents have normal renal evaluations, the empirically determined recurrence risk is approximately 3%. If one of the parents has unilateral renal agenesis, the recurrence risk may be as high as 50% because of a presumed autosomal dominant gene.

Preauricular pits and tags are minor anomalies that occur in about 0.3–1.0% of persons, with a wide variance in frequency among racial groups ( Fig. 11-6). They are twice as common in females as in males and can be inherited as an autosomal dominant trait. They are believed to represent remnants of early embryonic bronchial cleft or arch structures. As isolated findings, they do not warrant additional evaluations.

This designation is made when the upper portion of the ear (i.e., helix) meets the head at a level below a horizontal line drawn from the lateral aspect of the palpebral fissure. The best way to measure is to align a straight edge between the two inner canthi and determine whether the ears lie completely below this plane. Normally, approximately 10% of the ear is above this plane. ¹⁴

OI is a disease of bone, in which the affected neonate with osteogenesis imperfecta type II or III often manifests severe fractures prenatally, at birth, or shortly after birth. Although the disease has several levels of severity, in its most problematic forms growth is significantly impaired and life expectancy is very short. The primary component of sclera in humans is collagen. Given that abnormal collagen formation is the underlying defect in many of these disorders, it is not surprising that in OI types I, II, and III and many other connective tissue diseases the sclerae are abnormally thin and transparent. The bluish color of the sclera in patients with connective tissue (especially collagen) diseases is thought to be caused by visualization of the bluish uvea (the eye layer behind the retina) as seen through a more transparent sclera.

There is a genetic blood test for OI, and skin biopsies are no longer routinely required for testing. COL1A1 and COL1A2 are the two genes associated with OI types I, II, III, and IV. Mutation detection rates are approximately 100% for OI type I, 98% for OI type II, 60% to 70% for OI type III, and 70% to 80% for OI type IV.

Most cases of cleft lip and palate are inherited in a polygenic or multifactorial pattern. The male-to-female ratio is 3:2, and the incidence in the general population is approximately 1 in 1000. The recurrence risk after one affected child is 3% to 4%; after two affected children, it rises to 8% to 9%.

If an imaginary third eye would fit between the eyes, hypertelorism is possible. Precise measurement involves measuring the distance between the center of each eye’s pupil. This is a difficult measurement in newborns and uncooperative patients because of eye movement. In practice the best way to determine hypotelorism or hypertelorism is to measure the inner and outer canthal distances, then plot these measurements on standardized tables of norms.

Colobomas of the iris result from abnormal ocular development and embryogenesis. They are frequently associated with chromosomal syndromes, most commonly trisomy 13, 4p-, 13q-, and triploidy. In addition, they may be commonly found in the CHARGE association, Goltz syndrome, and Axenfeld-Rieger syndrome ( Fig. 11-7). Whenever iris colobomas are noted, chromosome microarray is recommended.

In 97% of term infants, the posterior fontanel is normally the size of a fingertip or smaller. Large posterior fontanels can be seen in infants with congenital hypothyroidism, skeletal dysplasias, or increased intracranial pressure.

In the fetus hair follicles on the skin surface grow downward during weeks 10 through 16. During this time the brain and scalp expand outward in a domelike fashion, pulling the follicles in different directions, and at 18 weeks when the hair erupts, patterns are set. The “crown,” or parietal hair whorl, is the focal point of this outgrowth. At birth it is usually a few centimeters anterior to the posterior fontanel. Approximately 55% of single parietal scalp whorls are left of midline (presumably secondary to the larger size of the left brain), 30% are right-sided, and 15% are midline. Bilateral hair whorls are present in 5% of normal persons. Abnormal positioning of the hair whorl (particularly a posterior location) can be seen in microcephaly.

Mosaicism is the possession of multiple genetically different cell lines in a single person. Most chromosomal mosaicism involves the sex chromosomes and occurs because of defects in mitosis in an early embryo. Normally, chromosomes duplicate and separate equally in mitotic division. Mosaicism can occur when the chromosomes fail to separate (mitotic nondisjunction) or fail to migrate (anaphase lag). In general, the greater the proportion of abnormal cell lines, the more abnormal the phenotype. The earlier in embryonic development an abnormal cell is established, the higher the percentage of abnormal cells in that person.

The term chimera is derived from the Greek mythologic monster that, according to Homer, had the head of a lion, body of a goat, and tail of a dragon. In cytogenetic parlance chimerism is the presence of two or more cell lines in a person that are derived from two separate zygotes. The most common cause of chimerism is the mixing of blood from unlike-sexed twins, resulting in a karyotype of 46,XX/46,XY. Chimerism can also result from the admixture of cells from a nonviable twin into a surviving fetus or, rarely, from incorporation of two zygotes into a single embryo.

First cousins may share mutations in one or more deleterious recessive genes. They have one eighth of their genes in common, and their progeny are homozygous at one sixteenth of their gene loci. Second cousins have only a one in 32 chance of having genes in common. The risk that consanguineous parents will produce a child with a severe or lethal abnormality is 6% for first-cousin marriages and 1% for second-cousin marriages. Expanded carrier screening panels are available containing several hundred mutations that may be useful for consanguinseous couples before conception.

A chromosome translocation is a transfer of chromosomal material between two (or more) nonhomologous chromosomes. The exchange is usually reciprocal (the two segments trading places). The genetic content of the person is therefore complete but rearranged. A Robertsonian translocation represents a special variety of chromosome translocation in which the long arms of two acrocentric chromosomes (13, 14, 15, 21, or 22) fuse at their centromeres. The breaks may occur within, above, or below the centromeres. The short arms are usually lost, but this does not produce an abnormality because the genetic material on the short arms of acrocentric chromosomes occurs in multiple copies throughout the genome. A phenotypically normal person with a Robertsonian translocation has only 45 chromosomes inasmuch as the long arms of two acrocentric chromosomes are fused into one.

Uniparental disomy is an inheritance pattern in which a child receives two identical chromosomes from one parent and none from the other. The most likely explanation is an abnormality in meiosis whereby one gamete receives an extra copy of a homologous chromosome owing to an error in separation. This gamete with two copies from one parent then unites with the gamete of the other parent. If the second gamete lacks that particular chromosome (i.e., nullisomic gamete), a normal karyotype results. If the second gamete contains that particular chromosome, a trisomic zygote results. During embryonic development this trisomy may be lost, resulting in a normal karyotype. UPD has been reported in some patients with Prader–Willi, Angelman, and Beckwith–Wiedemann syndromes as well as cystic fibrosis.

In this case a genetic male with a normal number of chromosomes has a reciprocal translocation between the short arm of chromosome 4 at band 21 and the long arm of chromosome 8 at band 22.

See Table 11-4.

Rarely, yes. If anaphase lag (loss) of a Y chromosome occurs at the time of cell separation into twin embryos, a female fetus with karyotype 45,X (Turner syndrome) and a normal male fetus (46,XY) result.

Monozygotic twins can be monochorionic monoamniotic, monochorionic diamniotic, or dichorionic diamniotic. Dizygotic twins will be dichorionic diamniotic.

Only infants with Turner syndrome have physical features easily identifiable at birth.

Fragile X syndrome is most common.

When the lymphocytes of an affected male are grown in a folate-deficient medium and the chromosomes examined, a substantial number of X chromosomes demonstrate a break near the distal end of the long arm. This site, the fragile X mental retardation 1 gene (FMR1), was identified and sequenced in 1991. At the center of the gene is a repeating trinucleotide sequence (CGG) that in normal persons repeats between 6 and 45 times. However, in carriers the sequence expands to between 50 and 200 times (called a premutation), and in fully affected persons it expands to between 200 and 600 copies. These longer sequences cause malfunctioning of the gene. The repeat expansion is most sensitively and accurately determined by Southern blot analysis. Male as well as female subjects can be affected, although it is an X-linked disorder.

Premature ovarian failure is one potential manifestation.

Isolated aniridia is most commonly caused by mutations in PAX6 and is prognostically associated with a multitude of ophthalmologic abnormalities that significantly impair vision but do not result in involvement of other organ systems. A contiguous gene deletion of 11p13 can produce syndromic aniridia associated with WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and retarded growth and development). When initially diagnosing a neonate with aniridia, it may not be obvious at birth whether this will be isolated or syndromic, and genetic testing for these two disorders is useful to determine the prognosis and the potential for associated problems.

Short femurs, IUGR, congenital heart disease, pyelectasis, echogenic cardiac focus, echogenic bowel, choroid plexus cyst, and cystic hygroma are all associated with aneuploidy.

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), a fatty acid oxidation disorder.

Conotruncal defects such as tetralogy of Fallot, interrupted aortic arch, truncus arteriosus, and ventricular septal defects are associated with DiGeorge syndrome.

Cleft lip, cleft palate, hypothyroidism, hypocalcemia owing to hypoparathyroidism, immunodeficiency with thymus hypoplasia and altered T cell function, failure to thrive, and developmental delay are also associated with DiGeorge syndrome.

Smith–Lemli–Opitz syndrome (congenital heart disease and genitourinary anomalies), peroxisomal disorders (congenital heart disease, epiphyseal stippling, renal cysts, CNS malformations), congenital disorders of glycosylation (CNS malformations, renal cysts, genitourinary anomalies), and fatty acid oxidation disorders (renal cysts; hypertrophic cardiomyopathy; CNS malformations, including cerebellar hypoplasia).

Fragile X syndrome, myotonic dystrophy, Huntington disease, spinocerebellar ataxia, and spinal bulbar muscular atrophy (Kennedy disease).

Prader–Willi syndrome, congenital myopathy or muscular dystrophy, myotonic dystrophy, and inborn error of metabolism.

You would examine the mother for evidence of a myopathic face, difficulty with speech or swallowing, myotonia and inability to release her grip, or cataracts. The AGC/CTG repeat size is unstable and much more likely to expand when transmitted through a female patient than through a male patient. As the repeat increases in size, the severity increases, and age of onset decreases.

If the long QT syndrome is genetically based, it is most likely to be autosomal dominantly inherited, putting the baby at 50% risk of long QT syndrome. The baby should be screened by electrocardiograph, and the QTc interval should be calculated. If it is prolonged more than 440 msec, the baby should be started on beta blockers. Additionally, genetic testing is now available for long QT syndrome, a genetically heterogeneous disorder caused by mutations in at least 12 currently known genes. Once a familial mutation is identified, the baby can be tested to determine whether he or she has inherited the mutation. Electrocardiographic screening is not perfectly sensitive, especially in children. Whenever possible, genetic screening of the at-risk child should always be performed to increase the sensitivity and specificity of screening. Additionally, medical management and risk of sudden cardiac death depends on which of the genes is affected and is definable only with genetic testing.

A marker chromosome is a small piece of a chromosome seen on routine karyotype that is hard to define by conventional cytogenetics.

This depends on the genetic content of the marker chromosome. If it contains a significant number of genes, it is more likely to be associated with birth defects, growth problems, and intellectual disability.

A chromosome microarray should be performed to define the source of the marker and characterize the gene content. If the genetic material is derived from chromosome 6, 7, 11, 15, or 16, uniparental disomy testing for that chromosome should be performed to rule out associated imprinting disorders observed with UPD of those chromosomes.

Mutations in the autosomal recessive genes GJB2 and GJB6 account for approximately 50% of cases of nonsyndromic hearing loss, and genetic testing for hearing loss should start with these genes. Genetic testing for a panel of genes associated with the most commons forms of syndromic and nonsyndromic hearing loss is also available and can be helpful to diagnose Pendred and Usher syndromes before other manifestations become apparent.

The diagnosis is most likely tuberous sclerosis complex (TSC). Cardiac rhabdomyomas are present in 47% to 67% of individuals with TSC. These tumors regress with time and eventually disappear and are largest during the neonatal period. Surgical intervention immediately after birth is necessary only when cardiac outflow obstruction occurs.

TSC is autosomal dominantly inherited and caused by mutations in TSC1 (31%) and TSC2 (69%). Molecular genetic testing for both genes is available on a clinical basis both prenatally and postnatally.

TSC involves other organ systems, including abnormalities of the skin later in life (facial angiofibromas, shagreen patches, ungual fibromas); cortical tubers in the brain; seizures; intellectual disability or developmental delay; kidney problems (angiomyolipomas, cysts, renal cell carcinomas); and, rarely, lymphangioleiomyomatosis in the lungs.¹⁵

The fetus most likely has polycystic kidney disease. If both parents have normal renal ultrasounds, this is most likely autosomal recessive polycystic kidney disease (ARPKD). The diagnosis can be confirmed with molecular genetic testing for PKHD1, the only gene known to be associated with ARPKD. In the prenatal and neonatal period there are enlarged echogenic kidneys. Approximately 45% of infants also have liver abnormalities. Pulmonary hypoplasia resulting from oligohydramnios is common. Approximately 30% of affected infants die in the neonatal period or within the first year of life, primarily as a result of respiratory insufficiency or superimposed pulmonary infections. More than 50% of affected children progress to end-stage renal disease, usually in the first decade of life.

Fetal _ Neonatal Secrets 3e