The Nature of Chromosomes

Productive insights gleaned from the results of the completed Human Genome Project have dramatically changed some of our understanding of how the human genome functions. However, it is important to introduce to the reader our current understanding of the subject matter. Human hereditary factors are located in genes (the genome). Approximately 10% are genes that encode proteins that are assembled to form tissue structures or to form enzymes that catalyze chemical reactions within cells. The other 90% have functions that are currently not clear (see also The Nature of Genes and Single-gene Disorders, later). The genes are composed of DNA and are stored in intranuclear cell organelles called chromosomes. Each chromosome contains one linear DNA molecule folded over onto itself several times, as well as ribonucleic acid (RNA) and proteins. Because all genes exist in pairs, all chromosomes must likewise exist in pairs. The members of each pair of genes are called alleles, and the members of each pair of chromosomes are known as homologues. The conventional depiction of the constitution of homologues in the nucleus is called the cell’s karyotype (Fig. 1-1). If at any gene locus the alleles are identical, that gene locus is homozygous. If the alleles are not identical, the gene locus is heterozygous.

Figure 1-1 Photomicrographs show that this is a G-banded male karyotype. (A female would have two X chromosomes and no Y chromosome.) The horizontal banding produced by the Giemsa staining technique allows for precise identification of homologous chromosomes.

(Courtesy Urvashi Surti, PhD, Pittsburgh Cytogenetics Laboratory.)

Except for gametes, normal human cells contain 23 pairs of chromosomes, 46 in all. One of these pairs is concerned in part with inducing the primary sex of the embryonic gonads. These sex chromosomes are called the X and Y chromosomes, and they are not genetically homologous except in a few areas. Women have two X chromosomes, whereas men have an X and a Y chromosome. The remaining 22 pairs are called autosomes and they determine non–sex-related (somatic) characteristics.

During most of a cell’s life cycle, chromosomes are diffusely spread throughout the nucleus and cannot be identified by morphologic means. Only when the cell divides does chromosome morphology become apparent (Fig. 1-2). The in vitro life cycle and the cellular division, or mitosis, of a somatic cell are illustrated in Figures 1-3 and 1-4, respectively. The life cycle and divisions, or meiosis, of a germ cell are much more complex and are not suitable for ordinary clinical evaluation.

Figure 1-2 Morphology of a chromosome during metaphase. A, Metacentric chromosome with centromere (3) in the middle. B, Submetacentric chromosome with centromere off-center. C, Acrocentric chromosome with centromere near one end. D, Telocentric chromosome (not found in humans) with centromere at one end. The DNA of the chromosome has replicated to form two chromatids: 1p and 1q represent one complete chromatid, 2p and 2q the other complete chromatid (p refers to the short arm and q refers to the long arm). The chromosome will then divide longitudinally, as shown in (B).

Figure 1-3 The in vitro life cycle of a somatic cell. Interphase lasts 21 hours and can be divided into the following three stages: G₁ (7 hours)—cell performs its tasks; S (7 hours)—DNA replicates; G₂ (7 hours)—cell prepares to divide. Then mitosis occurs.

Figure 1-4 Mitosis lasts about 1 hour, during which time the cell divides. A, Interphase cell at the end of G₂. B, Prophase: replicated DNA condenses and is visible. C, Metaphase: 46 duplicated chromosomes align randomly on the spindle and can be photographed for karyotyping. D, Anaphase: chromosomes divide longitudinally, and half of each one moves to the opposite pole of the cell. E, Telophase: cell wall divides. F and G, Interphase at G₁: two daughter cells, each with 46 chromosomes.

Any somatic cell that can divide in tissue culture can be used for chromosomal (cytogenetic) analyses. The most convenient tissue source is peripheral blood, from which lymphocytes can be stimulated to divide during 2 or 3 days of incubation in tissue culture medium. Fibroblasts obtained from skin remain a frequently used alternative when peripheral blood lymphocytes are not clinically suitable, but fibroblasts require an incubation period of 4 to 6 weeks. After death, lung tissue is the best tissue to culture for chromosomal analyses, although the process also requires a 4- to 6-week incubation period. Alternatively, skin fibroblasts are frequently obtained postmortem for various enzymatic and cytogenetic analyses, which may be used to confirm a clinical diagnosis. When a treatment decision requires urgency, preliminary chromosomal evaluation can be made within 4 to 24 hours by using uncultured bone marrow aspirate. Oftentimes the karyotype is supplemented within 48 to 72 hours by a molecular cytogenetics technique, either interphase or metaphase fluorescence in situ hybridization (FISH), using rapid culturing and diagnostic techniques. More recently, conventional cytogenetics is being substituted by high-resolution molecular karyotyping using microarray-based comparative genomic hybridization (array-CGH). Array-CGH enables copy number changes at high resolution. This is implemented in the clinical setting and is being recommended as the first step in the investigation of patients with developmental delays, mental retardation, and multiple congenital anomalies. FISH and other molecular techniques are now used primarily to confirm the imbalances detected by array-CGH. This is an ever-evolving area, and pediatric clinicians are advised to discuss clinical and laboratory investigations with clinical geneticists and/or laboratory directors before the initiation of tissue sampling to ensure the most productive use of samples and rapid testing methods.

Aneuploidy

Aneuploidy refers to an abnormality in chromosome number, in humans a chromosome number different from an even multiple of 23 (the haploid number) (Fig. 1-5). In aneuploidy there are typically 45 or 47 chromosomes instead of the usual 46. Rarely, multiples of the X or Y chromosome result in individuals with 48 or 49 chromosomes. Double aneuploidy, the simultaneous occurrence of two nondisjunctional events, has been described in the literature. In the liveborn, it usually involves one autosome and one sex chromosome. Double autosomal trisomy has been found repeatedly in spontaneous abortion but has not been demonstrated in a liveborn infant.

Figure 1-5 Karyotype of a patient with trisomy 13 demonstrates aneuploidy. Note the extra chromosome 13, causing the cell to have 47 instead of 46 chromosomes.

(Courtesy Urvashi Surti, PhD, Pittsburgh Cytogenetics Laboratory.)

If aneuploidy occurs in a gamete as a result of an error of chromosomal division (nondisjunction or anaphase lag) during meiosis, all cells are affected in the fertilized embryo. With subsequent pregnancies, the risk for another chromosomal abnormality in the offspring is increased approximately 1% to 2% overall, in addition to the general background risk of abnormalities. The couple would be at risk for aneuploidy states of many types, not just the particular aneuploidy in their affected child. We are not yet aware of the underlying mechanism for the increased risk; however, families may benefit from an understanding of the possibilities for prenatal diagnosis in their individual case and may want to be referred for genetic counseling before the conception of another child (Fig. 1-6, A–C).

Figure 1-6 A female, 3 years and 8 months old, with double aneuploidy: aneuploidy depicted by cytogenetic studies. Karyotype and FISH studies show predominantly 47XXX; some 47XXX also have an extra 21 (48XXX+21). The patient has some features of Down syndrome. Note the up-slanted palpebral fissures (A), low-set ears (B), and unilateral simian crease (C). An echocardiogram showed a patent foramen ovale. The patient is receiving behavioral and speech therapy; she is not toilet trained and has an individualized education program (IEP) in preschool. Triple X females are tall and mosaic Down syndrome is similar to full Down syndrome but with a much milder phenotype. Her weight was in the 95th percentile, her height in the 80th, and occipital–frontal circumference (OFC) in the 20th.

Mosaic Aneuploidy States

Mosaicism, the presence of two or more genetically different cell lines within an individual, can result from an error in division during either meiosis or mitosis. In one possible scenario aneuploidy originates during meiotic division (i.e., before conception). In such cases the fetus starts out with an aneuploid chromosomal number and, subsequently, a division error occurs, resulting in the formation of another cell line that is chromosomally normal. In other cases of mosaicism the one-celled embryo (zygote) is chromosomally normal and a division error occurs after fertilization, during mitosis of an embryonic somatic cell, resulting in aneuploidy. Most individuals with mosaicism have only two or three different lines of embryonic cells. It requires considerable laboratory investigation to distinguish the meiotic or mitotic types. Generally speaking, parents are given a 1% to 2% recurrence risk because of the possibility of mosaicism present in a parental gonad, which is not identifiable in usual tissue sample analyses (Fig. 1-7).

Figure 1-7 A 1-year-old with facies suggestive of Down syndrome. Note the facies and short fifth fingers and clinodactyly. The muscle tone and growth parameters were normal. Cytogenetics studies showed 2% of the cells with 47,XY+21; interphase fluorescence in situ hybridization (FISH) studies with an extra cell count showed trisomy 21 in 1.3% of 523 peripheral lymphocytes analyzed.

Hypomelanosis of Ito is characterized by marbleized or mottled areas of hypopigmented whorls of skin along the Blaschko lines and is of heterogeneous etiology. Individuals with hypomelanosis of Ito can have multiple congenital anomalies, dysmorphic features, variable mental retardation, and other neurologic findings. Karyotyping from skin lesions will reveal mosaic abnormality of chromosomes from normal or hypopigmented and hyperpigmented regions. Balanced and unbalanced chromosome aberrations and uniparental disomy may be encountered (Fig. 1-8).

Figure 1-8 Hypomelanosis of Ito. Karyotype at birth was normal: 46,XX. At 4 months of age characteristic streaks and whorls of hyper- and hypopigmentation of the skin were noted. A higher cell-count karyotype showed mosaicism for trisomy 14.

Abnormalities of Chromosome Structure

Chromosomes can be normal in number (diploid) but still be abnormal in structure. Inversions (Fig. 1-9), deletions (Fig. 1-10), and translocations (Fig. 1-11) of genetic material are examples of structural chromosomal abnormalities. These can arise as new (sporadic) mutations in the egg or sperm from which the embryo was formed, in which case the parents’ recurrence risk for another child with a chromosomal abnormality is again 1% to 2%. However, the abnormality may also be inherited from a phenotypically normal parent who is a “carrier” of a structural chromosomal abnormality (Fig. 1-12). About 1 in 520 normal individuals carries a balanced but structurally abnormal set of chromosomes, called a chromosome translocation. The term balanced, for the purposes of this chapter, means that on cytogenetic analysis the structural abnormality does not appear to have resulted in any net loss or gain of genetic material. If the apparently balanced chromosomal abnormality has been transmitted by other members of the family who are apparently phenotypically normal, it is considered a familial balanced translocation. Data suggest that a small percentage of individuals with apparently “balanced” translocations are actually mildly affected clinically by variable degrees of cognitive and physical deficits (Warburton, 1991). Thus high-resolution chromosome analyses and molecular cytogenetics techniques, such as array-CGH, are warranted in these instances including, as needed, in situ hybridization techniques using DNA probes to completely characterize the location of the chromosome breakpoints and to determine on a molecular level whether any genetic material is missing. Molecular studies for imprinting effects may also be warranted.

Figure 1-9 Pericentric inversion (arrow) of chromosome 13.

Figure 1-10 Deletion (arrow) of the p arm of chromosome 5 (cri du chat syndrome).

(Courtesy Urvashi Surti, PhD, Pittsburgh Cytogenetics Laboratory.)

Figure 1-11 Unbalanced translocation. The additional DNA was translocated onto the q arm of chromosome 5. The abnormality was inherited from a normal carrier father (see Figure 1-12) with a balanced reciprocal translocation between the q arms of chromosome 3 and chromosome 5. The patient died of multiple birth defects and in essence had a partial trisomy of the distal portion of the q arm of chromosome 3.

Figure 1-12 A “balanced” reciprocal translocation from chromosomes 3 to 5 in a normal man (the father of the chromosomally defective newborn whose karyotype is shown in Figure 1-11).

A frequent way in which families with apparently balanced chromosome translocations present for evaluation occurs when a child is born with structural malformations and on karyotyping is found to have an unbalanced chromosome translocation. This may have occurred de novo in the child’s chromosomes only or may be due to a previously undiagnosed familial balanced chromosomal translocation in a parent. Parental karyotypes are used to distinguish the etiology and are crucial in providing accurate genetic counseling regarding future pregnancies for that couple.

Incidence of Chromosomal Abnormalities

Data from Hook (1992) suggest that upward of 50% of human conceptions terminate in a spontaneous abortion. Most of these miscarriages occur so early during gestation that the pregnancy is never recognized. The earlier the abortion occurs, the more likely it is that the miscarried embryo had a chromosomal abnormality. Of recognized first-trimester abortuses, 50% are chromosomally abnormal, compared with 5% of later embryos. Among the chromosomally abnormal abortuses, the most frequent abnormalities are triploidy (69 chromosomes), trisomy 16, and 45,X (Turner syndrome) (Table 1-1). Generally speaking, triploidy and trisomy 16 are not compatible with life and are only occasionally seen among liveborn infants. Despite the fact that Turner syndrome is relatively common among liveborn infants, the majority of conceptuses with 45,X also abort spontaneously. The incidence of chromosomal abnormalities among liveborn infants in general is about 6 in 1000. Among a group including both stillborn infants and infants who die in the immediate perinatal period, the number is increased to approximately 50 in 1000.

Table 1-1 Occurrence of Chromosomal Abnormalities

When to Suspect a Chromosomal Abnormality

Chromosomal abnormalities of either number or structure are likely to have a detrimental effect on the phenotype of an affected individual. Aneuploidy of an autosome, or nonsex chromosome, generally significantly impairs physical and cognitive development. However, aneuploidy of a sex chromosome may have little or no apparent effect on the phenotype. One should look for clustering of abnormalities in family members to suggest a problem, although their absence does not rule out a chromosomal abnormality.

Carriers of an inherited or a de novo reciprocal translocation are usually genetically balanced and are subsequently normal. However, their conceptuses are likely to be genetically unbalanced and may abort spontaneously or be born with major congenital anomalies. A history of unexplained infertility, multiple spontaneous abortions (three or more), and particularly of a previous birth to the couple or to a close relative of a child with dysmorphic findings and/or major anomalies may be an indication that one of the parents carries a balanced chromosomal translocation or rearrangement. A chromosome study on the couple is thus indicated, and if translocation is found, they should seek antenatal genetic counseling. This may also be advisable for extended family members.

A normal person who carries a balanced reciprocal translocation can commonly produce six chromosomal types of gamete. On fertilization, these gamete types can result in several possible fertilized embryos: a normal conceptus, a carrier conceptus like the normal carrier parent, two types of immediately lethal conceptus resulting from gross chromosomal imbalances (i.e., too much or too little DNA), or two types of abnormal conceptus caused by lesser chromosomal imbalances. Whether the latter two types abort spontaneously or come to term as liveborns cannot be predicted in advance solely on theoretical grounds. Therefore genetic counseling in such situations depends somewhat on analysis of what has occurred within the individual family and in other families with similar rearrangements. Rarely, other types of chromosomal imbalances are found in conceptuses of such carrier parents.

Experience suggests the following: If a carrier has already produced a chromosomally unbalanced liveborn child, then it is apparent that it is possible for this to occur again in future pregnancies, and the risk that the translocation carrier might have another chromosomally unbalanced liveborn infant can be as high as 20%. However, if the translocation carrier parent has produced either only healthy liveborn infants or spontaneous miscarriages, then it is less likely that the chromosomally unbalanced gametes are viable. Consequently, that person’s risk for producing a chromosomally unbalanced liveborn is only about 4%. Last, if a couple of whom one spouse is a carrier has not yet experienced any pregnancies, their risk for a chromosomally abnormal liveborn is estimated to be about 10%.

Down Syndrome

The worldwide incidence of Down syndrome among liveborns is approximately 1 in 660, with 45% of affected individuals born to women older than 35 years of age. The incidence of Down syndrome among conceptuses is far greater than among liveborns because the majority of Down syndrome fetuses spontaneously abort.

No single physical stigma of Down syndrome exists; rather, the clinical diagnosis rests on finding a recognizable constellation of clinical characteristics including a combination of major and minor anomalies (Fig. 1-22).

Figure 1-22 Down syndrome. These clinical photographs show several minor anomalies associated with this disorder. A, Characteristic facial features with up-slanting palpebral fissures, epicanthal folds, and flat nasal bridge. B, Brushfield spots. C, Bridged palmar crease, seen in some affected infants. Two transverse palmar creases are connected by a diagonal line. D, Wide space between first and second toes. E, Short fifth finger. F, Small ears and flat occiput.

The most frequent features are up-slanting palpebral fissures and small external ears (by length). Several major anomalies are commonly associated with Down syndrome. Congenital heart disease is found in 45% of cases, particularly atrioventricularis communis and ventricular septal defects. Hence all newborns with Down syndrome should undergo cardiac evaluation with echocardiogram. About 5% have a gastrointestinal anomaly, most commonly duodenal atresia or Hirschsprung’s disease. An increased incidence of thyroid disorders also exists, particularly of the autoimmune type. Thus regular testing of thyroid function is recommended. Acute and neonatal leukemias occur 15 to 20 times more frequently in people with Down syndrome than in the general population. In newborns, much of this is represented by transient leukemoid reactions, with complete remission being the most frequent outcome. Quantitative abnormalities are found in many enzyme systems. People with Down syndrome are shorter than family members and the general population and have premature graying of hair. As adults, most males are infertile, but females may reproduce and can have children who will also have Down syndrome approximately one third of the time.

Minor anomalies include brachycephaly; inner epicanthal folds; Brushfield spots; flat nasal bridge; a small mouth with protruding tongue that fissures with age; a short neck with redundant skin folds; single transverse palmar (simian) creases; clinodactyly of the fifth fingers, with single digital crease caused by hypoplasia of the middle phalanx; and wide spacing between the first and second toes. The number of such anomalies varies in any particular case.

With rare exceptions, individuals with Down syndrome are cognitively impaired. The degree of impairment varies, with intelligence quotients (IQs) ranging from 20 to 80. Most individuals function in the mild to moderate range of developmental delay. The advent of individualized programs of early intervention therapy, education, and sporting activities has resulted in much improved outcomes and individuals who are much more likely to function at the maximum of their developmental capabilities. Autopsy analyses of brains from individuals with Down syndrome have revealed the neuropathologic changes of Alzheimer’s disease in 100% of those older than 40 years. Nevertheless, only about 25% of older individuals with Down syndrome exhibit clinical manifestations of Alzheimer’s disease. The reason for the clinical–pathologic discordance is not known. However, there does tend to be a progressive loss of cognitive functioning after the fourth decade of life. Longevity, although less than that of the general population, has steadily increased over the years. Individuals with Down syndrome who do not have congenital heart disease may expect to live well into their 60s. The principal causes of death in children with Down syndrome are infection, congenital heart disease, and malignancy.

The etiology of Down syndrome is trisomy 21, the presence of an extra chromosome 21 either as a simple trisomy or as part of a chromosome 21 fused with another chromosome. These fused chromosomes are often robertsonian translocation chromosomes or isochromosomes. Cases of mosaicism, in which trisomy 21 cell lines coexist with cell lines with the standard 46 chromosomes, exist as well and may range in phenotype from normal to that typical of complete trisomy 21. An association between trisomy 21 and advanced maternal age is clear (Table 1-4).

Table 1-4 Maternal Age–Specific Risk for Trisomy 21 at Live Birth

About 5% of Down syndrome cases represent a centric fusion translocation between the long arm of a chromosome 21 and those of a 13, 14, 15, 21, or 22 acrocentric chromosome. Of these, about one third are inherited from a clinically normal, balanced carrier parent; in the remaining two thirds the translocation is new in the affected child. Chromosome studies should therefore be performed on the parents and appropriate family members of an individual with translocation Down syndrome. If a parent carries a 21/21 translocation, all liveborns will have Down syndrome; for the remaining 21/centric fusion translocations, the empiric recurrence risk for a Down syndrome liveborn is less than 2% if the father is the carrier and roughly 15% if the mother is the carrier. The parents of children with trisomy 21 may benefit from genetic counseling to determine their individual risk of having another child with Down syndrome or with other chromosomal abnormalities in future pregnancies.

Trisomy 13

Trisomy 13 is a relatively rare (1 in 5000) genetic condition caused by the presence of additional chromosome material from all or a large part of chromosome 13. The vast majority of embryos with classic trisomy for a complete 13th chromosome abort spontaneously, but approximately 5% survive to be liveborn. They have a severe, recognizable pattern of malformation that allows clinicians to suspect this etiology immediately (Fig. 1-23). The hallmark features are defects of forebrain development related to those seen in holoprosencephaly, aplasia cutis congenita, polydactyly (most frequently of the postaxial type), and narrow hyperconvex nails. A broader listing of features is outlined in Table 1-5, which can be useful in comparing the features frequently seen in infants with trisomy 13 with those seen in trisomy 18. As with many syndromes, trisomy 13 and trisomy 18 share structural abnormalities; however, they usually are distinguishable on the basis of the pattern of anomalies present. Liveborn infants with trisomy 13 represent those who have the least severe structural abnormalities of major organs. Of these, about 5% survive the first 6 months of life. Thus discussions with parents about surgical interventions must take into account the small possibility of long-term survival and require sensitivity to the needs of the child and family.

Figure 1-23 Several physical manifestations of trisomy 13. A, Facies showing midline defect. B, Clenched hand with overlapping fingers. C, Postaxial polydactyly. D, Equinovarus deformity. E, Typical punched-out scalp lesions of aplasia cutis congenita.

(A, Courtesy T. Kelly, MD, University of Virginia Medical Center, Charlottesville; B to E, courtesy Kenneth Garver, MD, Pittsburgh, Pa.)

Table 1-5 Physical Abnormalities and Frequencies of Occurrence in Trisomy 13 and Trisomy 18 Syndromes

Milder chromosome abnormalities involving extra material determined to originate from chromosome 13 must be identified and distinguished from classic trisomy 13 because the clinical phenotype and prognosis may be different and, in some cases, less severe. Children with mosaicism, that is, with a normal cell line and a trisomy 13 cell line, as well as those with trisomy of part of chromosome 13, can be identified by chromosome analysis. Careful laboratory investigation must be carried out to identify the exact chromosomal abnormality. The advent of FISH technology has dramatically increased the ability of laboratory specialists to characterize chromosome rearrangements, with the goal being to identify the exact breakpoints of the chromosomes involved in the rearrangements. Molecular studies then may be possible to determine any potential impact of the rearrangement on individual genes and their products. This information is extremely helpful to clinicians in determining prognosis and in providing more realistic information when discussing treatment options. Rarely, children who have the recognizable pattern of clinical features of trisomy 13 have normal chromosomes. If a geneticist/dysmorphologist is not already involved, a consultation is warranted to aid in diagnosis and prognosis counseling and to determine any recurrence risks for the parents in future pregnancies.

Trisomy 18

The chromosomal disorder trisomy 18 occurs in approximately 3 in 10,000 newborns, and females are more likely to be liveborn. Affected infants are small for gestational age and have a frail appearance, and the face tends to appear petite relative to the rest of the craniofacial contour (Fig. 1-24, A). They also have a recognizable pattern of malformation, but in these infants hallmark features—clenched hands with overlapping fingers (see Fig. 1-24, B), short sternum, and “low arch” fingerprint patterns—are minor anomalies. Major anomalies, especially congenital heart disease, are generally present as well and are the source of significant morbidity and mortality. Other common findings include a prominent occiput, low-set and structurally abnormal ears, micrognathia, and rocker-bottom feet (see Fig. 1-24, C). See Table 1-5 for a broader listing of clinical features that can be useful in distinguishing trisomy 18 from trisomy 13, which shares many of the same structural abnormalities.

Figure 1-24 Several physical manifestations of trisomy 18. A, Typical profile reveals prominent occiput and low-set, posteriorly rotated malformed auricles. B, Clenched hand showing typical pattern of overlapping fingers. C, Rocker-bottom feet.

(Courtesy Kenneth Garver, MD, Pittsburgh, Pa.)

Trisomy 18 was previously thought to be almost invariably fatal in the neonatal period; however, more recent data suggest that a small percentage of children can live longer, and that between 5% and 10% will be alive at their first birthday. Survivors are more frequently female and have less severe structural abnormalities of major organs than most affected infants. Even with optimal neonatal, pediatric, and surgical management and excellent home-based care, children with classic trisomy 18 often “fail to thrive” and have significant developmental and cognitive impairments. Discussions with parents about interventions must take into account the slim possibility of long-term survival and require sensitivity to the needs of the child and family. Great care must be taken in providing a balanced picture to the family when discussing treatment options.

Chromosome analysis allows clinicians to evaluate the etiology of the trisomy and can help determine prognosis. Results can demonstrate classic trisomy 18 due to a complete extra chromosome 18, mosaicism for trisomy 18, or a complex chromosome abnormality involving one or more chromosomes. Children with chromosomal rearrangements that result in partial rather than complete trisomy 18 may have a milder clinical outcome. Trisomy limited to the short arm of chromosome 18 is associated with a significantly milder prognosis, whereas trisomy of the entire long arm of chromosome 18 may be indistinguishable from an individual with classic trisomy 18. An infant with smaller areas of trisomy for the long arm of chromosome 18 may show some, but not all, of the features of classic trisomy 18. Thus chromosomal study of each child is essential.

If a complex chromosome rearrangement is identified in a child, further parental chromosome studies are indicated. Chromosome analysis of the parents will determine whether the rearrangement is new in the child (de novo) or is the result of a familial balanced translocation. Full characterization of the extent of a chromosome rearrangement also allows clinicians to provide more accurate information regarding prognosis, treatment options, and recurrence risk to the family. If a familial balanced translocation is present in one of the parents, other family members may benefit from genetic counseling to discuss recurrence risk and the availability of prenatal diagnosis for future pregnancies.

It has been our experience that parent support organizations can be extremely helpful to family members in the long process of adjustment to having a child with a chromosome problem. If the child dies, these groups can be helpful as a resource to the parents because of the similarity of their collective experience and can assist them in the grieving and healing process. They can also be a source of ongoing support and information to parents of a child with trisomy 13 or trisomy 18 who may live but who will face major medical and developmental challenges due to the chromosomal abnormality.

Turner Syndrome

Turner syndrome is one of the three most common chromosomal abnormalities found in early spontaneous abortions. The phenotype is female. About 1 in 2000 liveborn females has Turner syndrome. Primary amenorrhea, sterility, sparse pubic and axillary hair, underdeveloped breasts, and short stature ( to 5 ft) are the usual manifestations. Other external physical features may include webbing of the neck; cubitus valgus; a low-set posterior hairline; a shield chest with widely spaced nipples; and malformed, often protruding, ears (Fig. 1-25, A–E). Internally, renal anomalies may be present along with congenital heart disease, particularly bicuspid aortic valve (in 30% of cases) and coarctation of the aorta (in 10% of cases). Affected women have an infantile uterus, and their ovaries consist only of strands of fibrous connective tissue. Newborns often have lymphedema of the feet and/or hands (Fig. 1-25, D and E), which can reappear briefly during adolescence. Mental development is usually normal. Schooling and behavioral problems seem to be the same as in age-matched control subjects, although difficulty with spatial orientation such as map reading may be a problem. The classic physical findings of Turner syndrome may be absent, or the abnormalities may be so minimal in the newborn that the diagnosis is missed. The first indication may be unexplained short stature in later childhood or failure to develop secondary sex characteristics by late adolescence. Thus a chromosome study is indicated as part of the diagnostic workup of adolescent girls with these complaints.

Figure 1-25 Clinical photographs show several physical manifestations associated with Turner syndrome. A, In this newborn a webbed neck with low hairline, shield chest with widespread nipples, abnormal ears, and micrognathia are seen. B, The low-set posterior hairline can be better appreciated in this older child who also has protruding ears. C, In this frontal view mild webbing of the neck and small widely spaced nipples are evident, along with a midline scar from prior cardiac surgery. The ears are low set and prominent, protruding forward. D and E, The newborn shown in (A) also had prominent lymphedema of the hands and feet.

The karyotype in the majority of individuals with Turner syndrome is 45,X. Most often, the missing sex chromosome is paternally derived, so the risk of Turner syndrome does not increase with maternal or paternal age. Another 15% of individuals with Turner syndrome are mosaics (XO/XX, XO/XX/XXX, or XO/XY). The physical stigmata may be less marked in mosaics, some of whom may be fertile. If an XY cell line is present, the intraabdominal gonads should be removed because they are prone to malignant change. The remaining cases of Turner syndrome have 46 chromosomes including one normal plus one structurally abnormal X. The latter may have a short (p) arm deletion or may be an isochromosome duplication of the long (q) arm of the X chromosome; usually it is paternally derived. Cases of Turner syndrome with one normal and one abnormal X chromosome are more likely to have other, more serious major anomalies including cognitive deficits. A structurally abnormal X chromosome may lead to abnormal X inactivation resulting in a deleterious dosage effect for X-linked genes. Karyotypes such as 46,XYp- or 46,Xi(Yq) result in a female with Turner syndrome.

Moreover, loss of the short arm of an X chromosome results in full-blown Turner syndrome; deletion of the long arm usually produces only streak (fibrous) gonads with consequent sterility, amenorrhea, and infantile secondary sex characteristics without the other somatic stigmata of Turner syndrome. If the diagnosis is clinically suspected, a chromosome study should be ordered. Should the affected child be 45,X or a mosaic, the parental risk for recurrence of a chromosomally abnormal liveborn is 1% to 2% but may be higher if a parent carries a structurally abnormal X chromosome.

Antenatal diagnosis of chromosomally abnormal fetuses should be discussed with the parents, and the relatively good prognosis for Turner syndrome liveborns should not be overlooked. Girls with Turner syndrome should receive appropriate hormone therapy during adolescence to enable development of secondary sex characteristics and stimulate menses. Rarely, 45,X women with Turner syndrome have been fertile for a limited number of years.

Klinefelter Syndrome

One in 500 newborn boys has Klinefelter syndrome. The physical stigmata are subtle and usually not obvious until puberty, at which time the normal onset of spermatogenesis is blocked by the presence of two X chromosomes. Consequently the germ cells die, the seminiferous tubules become hyalinized and scarred, and the testes become small. Testosterone levels are below normal adult male levels, although the level varies from case to case (the average being about half as much as normal). Hence there is a wide range in degree of virilization. At one extreme is the man with a small penis and gynecomastia (Fig. 1-26); at the opposite extreme is the virile mesomorph with a normal penis. Scoliosis may develop during adolescence. The average full-scale IQ of men with Klinefelter syndrome is 98, which is about the same as the general population. Behavioral problems may be more common than in the population at large, however.

Figure 1-26 Clinical photographs show several physical manifestations of Klinefelter syndrome. A, Relatively narrow shoulders, increased carrying angle of arms, female distribution of pubic hair, and normal penis but with small scrotum due to small testicular size. B, Small testes and penis. C, Gynecomastia.

(B, Courtesy Peter Lee, MD, Hershey Medical Center, Hershey, Pa; C, from Gardner LI, editor: Endocrine and genetic diseases of childhood, ed 2, Philadelphia, 1975, WB Saunders.)