Rudolph's Pediatrics, 22nd Ed.

CHAPTER 174. Chromosome Disorders

John C. Carey

Chromosome disorders and their associated syndromes can be classified into abnormalities of chromosome number and chromosome structure as well as divided into conditions involving autosomes and those involving sex chromosomes.^1,2 Three autosomal trisomy syndromes involving chromosomes 21, 18, and 13 and the now well-recognized 22q11 deletion syndrome are the most common disorders involving the autosomes.

Abnormalities of chromosome structure involve duplication or deficiency of a chromosome region or a combination of both. The common deletion syndromes involving terminal (partial) monosomy of chromosomes 4p, 5p, 18p, and 18q were described in the 1960s. However, the introduction of banding techniques led to the recognition and delineation of many other partial monosomy and partial trisomy syndromes since then.¹ Whereas many of the phenotypic defects and syndromes caused by chromosome abnormalities have been cataloged, most of these disorders are typified by a consistent pattern of multiple anomalies, growth delays, and developmental disability.^1-3 In this section the most common trisomy conditions will be presented; selected deletion syndromes and other aneuploid conditions will also be reviewed.

Chromosome abnormalities occur in about 1 in 150 live births, are responsible for a substantial proportion of genetic diseases, are a major contributor to fetal loss, and are a significant cause of congenital malformations and mental retardation.² About 15% of all newborns with a congenital malformation and approximately 20% of persons with moderate to severe mental retardation have a chromosomal abnormality.⁴ Trisomy 21, the most common of the trisomy syndromes, accounts for more than one third of the infants born with a chromosome abnormality, and about 1 in 300 newborns will have an abnormality of one of the sex chromosomes. All the other autosomal disorders of number and structure combined have an overall frequency of less than 1/1000. Of note, balanced rearrangements such as translocations and inversions occur in about 1 in 500 individuals.

Each chromosome syndrome has its own natural history, list of component manifestations, and intrinsic variability. Most disorders of autosomes are associated with alterations of growth and development, such as developmental disabilities, prenatal growth deficiency, short stature, and microcephaly.¹ In addition, congenital heart defects are observed with increased frequency in all the well-established chromosome syndromes. Although the separate features of each chromosome syndrome are relatively non-specific, the total constellation of phenotypic findings in each of the more common syndromes is distinctive enough to permit clinical recognition.³ In particular, this is true of the common autosomal trisomy syndromes and well-established deletion syndromes. Moreover, it is usually the minor anomalies of structure and the alterations of facial morphogenesis that provide the clinical clues that alert the clinician to the possibility of a chromosomal syndrome. Furthermore, a remarkable consistency of the facial gestalt of children with a well-established syndrome at similar ages occurs and is clearly evident by examining photographs of different children with Down syndrome.^1,3

The phenotypes of chromosome disorders of structure vary considerably because of differences in the size of chromosome duplication or deficiency and the involvement of nonhomologous chromosomes. The clinical indications for performing cytogenetic analysis have become well established in the past three decades. Certainly all persons suspected of having a recognizable chromosome syndrome such as Down syndrome, Turner syndrome, or trisomy 18 need a karyotype. In addition, infants and children with unrecognizable patterns of multiple major and/or minor anomalies should have a karyotype to define the potential etiology of the condition. In recent years, most geneticists have recommended a cytogenetic analysis (usually by comparative genomic hybridization-CGH-microarray) in all children and adults with idiopathic mental retardation, regardless of whether the individual is dysmorphic.⁵ Although this recommendation is somewhat controversial, discovery of a chromosome abnormality, even an uncommon one, will assist the clinician and the family in understanding the condition and organizing medical management (see Chapter 185).

Other indications for performing a cytogenetic analysis in the pediatric setting are situations in which certain individual findings bring to mind specific conditions. Examples include stillborns with no recognizable reason for fetal death, proportionate short stature in a female (a feature of Turner syndrome), adolescent males with small testes or significant gynecomastia (features of Klinefelter syndrome), infants with hypotonia (Prader-Willi syndrome), and newborns with ambiguous genitalia. Cytogenetic analysis of parents whose children have structural chromosome abnormalities, such as deletions and duplications, is also indicated. Karyotyping is usually not indicated in an infant or child with a single malformation (eg, a neural tube defect or cleft lip) or in the parents of children with a recognized trisomy syndrome (eg, trisomy 21). The issue of which study to perform, that is, high-resolution banding or targeted fluorescence in situ hybridization (FISH) and comparative genomic hybridization microarray (array CGH), is discussed in Chapters 173 and 185.

COMMON TRISOMY SYNDROMES

The most common autosomal chromosome syndromes are trisomy 21, 18, and 13. The 22q11 deletion syndrome is probably as common as trisomy 18. Complete trisomy of other chromosomes such as 7, 8, 9, and 22 has been described in live-born infants, although most individuals with these conditions are mosaic for the trisomic cell line. Table 176-1 provides further information on these less-common chromosome syndromes.^1,3

TRISOMY 21 (DOWN SYNDROME)

Down syndrome is caused by trisomy 21 and is the most common autosomal chromosome abnormality in humans.⁶ The condition occurs in about 1 in 800 infants and is the most common multiple congenital anomaly/mental retardation syndrome. The use of the term mongolism is no longer appropriate, because this designation is considered pejorative and stigmatizing. The etiology of Down syndrome is related to trisomy of the distal part of the long arm of chromosome 21. More than 90% of individuals with Down syndrome will have three copies of the entire chromosome 21, while less than 10% will have trisomy of only part of the long arm of chromosome 21. The latter is usually caused by unbalanced Robertsonian translocation (see Chapter 173).

The phenotypic pattern of Down syndrome is characteristic and consistent enough to permit recognition of an affected neonate.⁶ Most of the facial and limb features of individuals with Down syndrome are not morphologically abnormal, but the specific constellation of manifestations is distinctive. The well-known list of phenotypic variations and minor anomalies is described in many sources and will not be summarized here. The brachycephaly, small ears (less than 3.2 cm in longest length in the newborn), upslanted palpebral fissures, flat midface, full cheeks, and distinctive shape of the mouth when crying are very consistent and together evoke a distinctive gestalt in a child of virtually any age. Small ears and hypotonia are observed in more than 90% of newborns with Down syndrome. Although epicanthal folds and a single transverse crease (the so-called simian line, a less-preferred designation) are commonly sought when considering the syndrome, these features are not only nonspecific but also occur in only about 50% of persons with Down syndrome. Short, broad fingers (brachydactyly), absent to very small nipple buds, and a central placement of the posterior hair whorl are more specific to Down syndrome than many other well-known findings. Systems for scoring the clinical findings of children in whom the diagnosis of Down syndrome is being entertained have been developed but are rarely needed because of the ease of recognizing most infants with the syndrome (Fig. 174-1 and eFig. 147.1 ).

Congenital heart malformations occur in about 40% of children with Down syndrome.^6,7 About one-third of these malformations fall within the spectrum of an atrioventricular (AV) canal defect and about one third are ventricular septal defects. Atrial septal defects of the secundum type and tetralogy of Fallot also occur, although they are less frequent. Because a heart murmur is frequently not present in a child with an AV canal defect, clinical examination alone is not enough to exclude the presence of a heart malformation in children with Down syndrome. Referral for an echocardiogram is now considered part of routine health supervision of infants with Down syndrome. If the diagnosis of a shunt lesion is missed in infancy, the early development of pulmonary hypertension characteristically seen in infants with Down syndrome could preclude some surgical options.

Obstructive gastrointestinal lesions including duodenal atresia and Hirschsprung “disease” occur in about 5% of infants with Down syndrome. However, no investigative studies are recommended unless an infant is symptomatic. Congenital cataracts occur in only about 5% of newborns as well, but other ocular problems (eg, strabismus, refractive errors) are common, warranting careful eye examinations in infancy. Other congenital malformations are uncommon in Down syndrome.

Individuals with Down syndrome, whether or not a heart defect is present, have an increased mortality rate compared with other children. The higher childhood mortality may, in part, be caused by an increased occurrence of infections, especially pneumonia. Abnormalities that affect the respiratory system, including gastroesophageal reflux, primary pulmonary hypertension, and obstructive sleep apnea, are often the basis for symptoms that occur in infancy including cyanosis, respiratory distress, apnea, and growth deficiency. Although a detailed evaluation of an infant with Down syndrome who has these symptoms is appropriate, a perspective on increased mortality needs to be communicated to families during the newborn period. For example, about 90% of children without heart defects will live into adolescence and early adulthood.

The degree of developmental disability in children with Down syndrome is quite variable, but children learn to walk and develop communication skills. The development of most children progresses steadily, albeit at a slower pace than usual. There is no evidence that function regresses during childhood or adolescence. Early intervention accelerates attainment of development skills in the preschool years, but the long-term effect of these programs on ultimate intellectual functioning is unknown. Nevertheless, referral to early intervention programs is recommended, because these programs help the family in areas other than acquisition of developmental skills by providing emotional support, information regarding the educational system, and feedback regarding a child’s individual developmental strengths and weaknesses.^6,8

FIGURE 174-1. An infant with Down syndrome, whose features are typical of this disorder: upslanting palpebral fissures, epicanthic folds, and a flat facial profile. (Source: Jorde LB, Carey JC, Bamshad MJ, White RL. Medical Genetics. St. Louis, MO: CV Mosby; 2000.)

Older persons with Down syndrome have an increased risk for a variety of medical problems including atlantoaxial subluxation, cataracts, diabetes mellitus, hypo- and hyperthyroidism, leukemia, and seizures.^6,7 Most of these problems occur infrequently, but the pediatric clinician should maintain a high level of suspicion. In the fourth decade of life, some adults with Down syndrome develop increasing cognitive dysfunction including a memory disorder. For this reason, baseline psychometric testing in the twenties is indicated in all young adults with Down syndrome.

Guidelines for health supervision and anticipatory guidance in infants, children, and adolescents with Down syndrome are available. The American Academy of Pediatrics (AAP) has published guidelines that are used commonly,⁷and specific recommendations include cardiac evaluation with echocardiogram before age 6 months; audiologic evaluation including tympanogram by age 6 months; newborn screening for hypothyroidism and periodic T4 and TSH throughout childhood and into adulthood; ophthalmologic evaluation at age 4; and routine immunizations. Monitoring of developmental progress and referral to early intervention or rehabilitative and educational services are axiomatic.

Various alternative therapies have been proposed in the treatment and management of infants and children with Down syndrome and information on risks and benefits of these therapies can discussed with parents.

Genetic Basis of Trisomy 21

Cytogenetic studies are recommended for all infants who have a clinical phenotype consistent with Down syndrome to rule out the few chromosome syndromes that could mimic Down syndrome (XXXY, partial 10q trisomy), especially in infancy, and to determine if the infant has three complete copies of chromosome 21 or a translocation involving chromosome 21.^1,6 This latter finding is important because the recurrence risk for parents varies dependent on the type of chromosome abnormality found in the affected child.

If a child with trisomy 21 is found to have three complete copies of chromosome 21, the risk that a mother under the age of 35 will have a second affected child with trisomy 21 is about 1 to 2%. Compared with the background risk of having a child with trisomy 21 (1/800, or 0.125%), this is an 8- to 16-fold increase for women who have had one child with trisomy 21. If a woman is over the age of 35, the recurrence risk is thought to be similar to the age-specific risk. Further cytogenetic testing of the parents is not indicated.

If a child with trisomy 21 is found to have an unbalanced translocation resulting in partial trisomy 21, cytogenetic analysis should be performed on the parents. If one of the parents carries a balanced translocation involving chromosome 21, the risk of recurrence will depend on the type of translocation and which parent is the carrier. Fathers carrying a balanced Robert-sonian translocation have a 1% to 2% recurrence risk, whereas mothers who carry it have a 10% to 15% recurrence risk. Families of children with Down syndrome caused by a translocation should be referred for genetic counseling. Prenatal testing of future pregnancies can be offered to the families of any child with trisomy 21.

The etiology and pathogenesis of trisomy 21 are unknown. The extra copy of chromosome 21 is thought to result from altered segregation of the chromosomes during meiosis, a phenomenon called nondisjunction, which may explain why the only factor that is consistent throughout all studies is that the prevalence of Down syndrome increases with advancing maternal age. No environmental factors have been implicated as causes for trisomy 21.

Counseling the Family of a Newborn with Down Syndrome

The pediatric practitioner often has the responsibility of informing parents that their newborn baby has Down syndrome. The approach to this situation is complex because every family differs in their expectations and preconceived notions about developmental disability and about the meaning of children within their family. The principles around these informing sessions and guidelines for effective and empathetic communications are outlined in Table 174-1.

Several retrospective studies on parents’ reactions to the birth of a child with Down syndrome indicate that families prefer to know the diagnosis as soon as possible.⁹ If the diagnosis is not in question and the infant does not have an associated life-threatening malformation, suggestions for planned counseling include the following: Arrange a private meeting with both parents together; avoid initiating the discussion while on an open postpartum ward or with other parents in the room; have the meeting sitting down with the family, as opposed to standing; refer to the infant by his or her first name if known; plan to meet the parents daily for the first few days of the infant’s life and set up a structure for these interviews; use the initial interview to present the diagnosis and the concept of a syndrome; be realistic but hopeful about the information; mention that all children with trisomy 21 have developmental disability but that it varies in degree; have current and accurate information on natural history, the developmental disability, and health supervision available; and avoid presenting details about the genetic basis of trisomy 21 at the initial interview. Information on issues such as the recurrence risk and feasibility of prenatal diagnosis is usually not appropriate to present at the first meeting unless parents specifically ask for it. This additional information can be presented at follow-up visits.⁹

Let the second interview attempt to assess the parents’ feelings and their state of mind. Create an opportunity to discuss their various reactions, listen to their personal concerns, and recognize individual feelings of each parent. When the results of the chromosome analysis are available, discuss any further implications and confirmation of the diagnosis. When the infant is being discharged, use the physical exam to emphasize the many normal aspects of the child as well as manifestations of the syndrome.

During the first few days after the diagnosis has been made, recall that parents are not only grieving the loss of an expected normal child but also going through the natural process of bonding to a newborn baby. After the first few interviews, the parents should be acquainted with community resources and can be referred to the appropriate agency or infant programs that deal with children with developmental difficulties. Many parents express particular interest during this time in meeting other parents who have a child with Down syndrome and to have accurate and current reading material. The internet offers hundreds of contact points regarding Down syndrome. The Web sites for two of the large support groups, Down Syndrome Society and Down Syndrome Congress, are excellent resources (http://www.nsds.organd http://www.ndsccenter.org). Referral to a local support group or parent-to-parent contact is always appropriate in these situations and has become a component of routine care.

Table 174-1. Recommendations for Performing Interviews in Giving Difficult News to Parents

Source: Adapted from Dent KM, Carey JC. Breaking difficult news in the newborn netting: Down syndrome as a paradigm. Am J Med Genet. 2006;142C:173-179.

Each family will proceed through this adjustment process at a different rate. Feelings of denial, anger, guilt, and sadness mixed with natural tendencies to bond to their newborn baby will affect the family’s understanding and perhaps even the reception of technical information.⁹ Over the past two decades, a clear trend toward presenting information in a hopeful and optimistic manner has been the approach rather than overemphasizing disabilities and problems. Eliminating the inappropriate and misleading stigma that has surrounded the diagnosis of Down syndrome for decades goes a long way toward improving parental adjustment in this setting. Dent and Carey⁹ reviewed the literature on this topic and suggested a theoretical model for practice and future research.

TRISOMY 18 (EDWARD SYNDROME)

The distinct pattern of malformation known as Edward syndrome caused by trisomy 18 is the third most common autosomal disorder and occurs in about 1 in 5000 to 6000 live-born infants. Trisomy 18 is also a common and important recognizable chromosomal cause of stillbirth, and among live-born cases, females comprise four times the number of cases as males. Similar to trisomy 21, trisomy 18 occurs with increased frequency as a woman ages. Infants with trisomy 18 have a recognized pattern of multiple congenital anomalies and an increased neonatal and infant mortality rate.¹⁰ The constellation of findings is as recognizable to the experienced clinician as Down syndrome (Fig. 174-2).

The pattern of abnormalities observed in infants with trisomy 18 consists of prenatal growth deficiency of length and weight, a distinctive face characterized by a high forehead, small facial structure and mouth, short sternum, and a characteristic set of hand findings consisting of overlapping fingers and hypoplastic nails (Fig. 174-2). Ninety percent of children with trisomy 18 have structural heart malformations, usually consisting of a ventricular septal defect with a polyvalvular dysplasia; some children will have more serious malformations such as hypoplastic left heart or a double outlet right ventricle.¹⁰

Neonatal and infant mortality are increased; 50% of children with trisomy 18 syndrome die in the first week of life, and about 90% have died by age 1. The cause of most infant deaths is probably central apnea. The common heart malformations observed in infants with trisomy 18 are rarely the sole cause of death but may contribute to early death of some children. Individuals who survive into later infancy and childhood consistently have a significant developmental disability. The degree of disability is marked enough that children with trisomy 18 do not usually walk unsupported or develop expressive language. However, all children progress slowly in attaining milestones, recognize their families, and demonstrate skills that are usually age-appropriate for a 6- to 12-month-old child. Some older children develop skills such as feeding themselves and understanding cause and effect comparable to the developmental age of a 2 year old.¹¹ The plight of families who have an infant with trisomy 18 is obviously overwhelming. Decisions to be made about management during newborn and early infancy are complex, and practitioners who care for families of children with trisomy 18 have both the challenge and the opportunity to support the parents in a memorable and significant manner. Carey has outlined these challenges and opportunities in a comprehensive review.¹⁰

FIGURE 174-2. A newborn girl with trisomy 18 (Edward syndrome). Note a short sternum, overlapping fingers with clenched fists, and a left-sided clubfoot. (Source: Jorde LB, Carey JC, Bamshad MJ, White RL. Medical Genetics. St. Louis, MO: CV Mosby; 2000.)

Ninety-five percent of infants with Edward syndrome have three copies of the entire chromosome 18. The remaining 5% have either mosaicism or partial trisomy of most of the long arm of chromosome 18. The chance for recurrence in future pregnancies is about 1% in families in which the mother is less than 35 years old, and it is most likely the age-specific risk for the older mothers. As in Down syndrome and all other chromosome syndromes, parents should be referred to a parents’ support group. The Support Organization for Trisomy 18, 13, and Related Disorders (SOFT) (http://www.trisomy.org) is a helpful resource for families of children with trisomy 18 and 13 and other chromosome syndromes that involve similar medical difficulties. The Trisomy 18 Foundation Web site (http://www.trisomy18.org) also provides information for families.

TRISOMY 13 (PATAU SYNDROME)

Trisomy 13, also referred to as Patau syndrome, is the fourth most common autosomal disorder in humans and has a prevalence of about 1/10,000 to 1/15,000 live births.¹⁰ The pattern of malformations observed in children with trisomy 13 is the combination of an orofacial cleft, microphthalmia, and posterior polydactyly of the limbs (Fig. 174-3). The entire spectrum of the facial characteristics associated with holoprosencephaly, ranging from cyclopia to premaxillary agenesis, can be seen in infants with trisomy 13. Similar to trisomies 18 and 21, congenital heart malformations are common in infants with trisomy 13 and occur in about 80% of affected infants. The prognosis for both survival and development is similar to that of children with trisomy 18. However, for infants with trisomy 13, the presence of holoprosencephaly is probably the single most important finding that predicts survival. To this end, it should be noted that most children with trisomy 13 who survive early infancy usually do not have holoprosencephaly (Fig. 174-3B).

FIGURE 174-3. A: Newborn showing the features of trisomy 13 (Patau syndrome). Note the bilateral cleft lip and broad nasal bridge and posterior polydactyly of the left hand. (Source: Jorde LB, Carey JC, Bamshad MJ, White RL. Medical Genetics. St. Louis, MO: CV Mosby; 2000.) B: An older child with trisomy 13. Note the repaired cleft lip.

Approximately 80% of children with trisomy 13 have three complete copies of chromosome 13, and most of the remaining cases have three copies of the long arm of chromosome 13 caused by an unbalanced robertsonian translocation.¹⁰ Only a few percent of children with trisomy 13 are mosaic. The recurrence risk for trisomy 13 is similar to that for trisomy 18. SOFT is also a resource for families of children with trisomy 13.

COMMON DELETION SYNDROMES

The first deletion or partial trisomy described in humans was 4p in 1961 and reports of children with 5p and 18p followed in 1963.¹ Deletions of the distal portions of chromosomes 4p, 5p, and 18q have well-characterized patterns of malformation. The chromosome syndrome catalog and the database of Schinzel¹ provide further details. Unlike the classical autosomal trisomy syndromes, the phenotypic spectrum of these and other partial monosomy and trisomy conditions varies substantially, contingent on the size of the extra or missing chromosomal segments and whether there is duplicated material from another chromosome present (eg, unbalanced translocation). Moreover, determination of natural history of these conditions is often complex because of the selection bias of case reports that tend to report the more unusual manifestations and findings from infants and young children.

Wolf-Hirschhorn syndrome (WHS) was first described in the early 1960s and is related to partial loss of material from the distal short arm of chromosome 4. The frequency is estimated to be about 1/50,000 births with a female predominance. Early case reports suggested that about one third of these children died in infancy, but there are now many adolescents and adults with WHS. A recent investigation from the United Kingdom indicates that more than 80% of infants with WHS survive the early years of life and stress the overstated mortality of the early work.¹²

The phenotype of WHS is quite characteristic and consists of pre- and postnatal growth deficiency, microcephaly, a characteristic appearance of the nose, hypertelorism, a short philtrum, and hypotonia. Congenital heart malformations are observed in about one half of cases. Problems in infancy consist primarily of severe feeding difficulties and a marked increased incidence of seizures, which occur in almost 90% of children with WHS. The severity of the seizures seems to diminish after the first few years of life, and they cease by age 10. The developmental disability of children with WHS is significant, but there are a number of older children who are able to walk unsupported and gain toilet control. A few children speak in phrases or sentences. Children with WHS should be monitored for visual and hearing problems when young and scoliosis as older children and adolescents. Similar to the autosomal trisomies, guidelines for routine supervision have been proposed, and there exists a support group for families of children with WHS. The 4p- Support Group in North America (http://www.4p-supportgroup.org) is a resource for families and several advocacy groups are located in Europe.

Cri-du-chat syndrome is caused by a deletion of the short arm of chromosome 5p and is one of the most well-known chromosome disorders because of the famous and distinctive cry.^1,3 Other than the cry, which is said to resemble the sound of a cat and is caused by an anatomic alteration of the larynx, none of the phenotypic abnormalities is specific. However, the facial characteristics are quite similar in early childhood, including a round face with telecanthus and mild down-slanting of the palpebral fissures. Major malformations are less common in 5p deletion syndrome than in the autosomal trisomes, although about 30% of children will have a heart defect. The degree of developmental disability is also significant, but similar to WHS, the original case reports probably reflected only the most severely affected children. The 5p- support group (http://wwwfivepminus.org) provides resources and support for families of individuals with the syndrome.

The 18q deletion syndrome, sometimes referred to as De Grouchy syndrome, is characterized by variable microcephaly and developmental disabilities.^1,3 Growth deficiency is also observed, although it is less frequent than in the other autosomal syndromes. The severity of abnormalities appears to be related to the size of the monosomic region (ie, a larger deletion is associated with more problems than is a smaller deletion). Craniofacial features include deep-set eyes and a notable mid-facial hypoplasia, producing a facial gestalt that is characteristic. The fingers are thin, and there are often prominent dimples at the elbow and shoulder joints. Major malformations are less common than in the autosomal trisomy syndromes, but narrowed or atretic ear canals are a hallmark of the condition, and the presence of this finding in a child with multiple minor anomalies should raise the suspicion of 18q deletion syndrome. The Chromosome 18 Registry (http://www.chromosome18.org) is an international support group for families of persons with 18q deletion syndrome and other related chromosome 18 syndromes.

MICRODELETION SYNDROMES

The microdeletion syndromes are exemplified by the 11p monosomy syndrome, which is characterized by aniridia and Wilms tumors, previously known as the WAGR syndrome, which is owed to haploinsufficiency of two identified genes, PAX6 and Wilms tumor 1 (WT1). The notion that these disorders may be caused by deficiency of contiguous genes in the deleted chromosome region led to the widely described concept of contiguous gene syndromes.^1,2 This particular term is used less often now because it became clear that almost all deletion syndromes fall to some extent under this umbrella.

One of the most exciting discoveries surrounding microdeletion syndromes was the recognition in the late 1980s that a deletion of chromosome 15q11 caused two separate conditions, Prader-Willi syndrome and the Angel-man syndrome, depending on whether the deleted region was on the paternal or maternal chromosome, respectively (Fig. 174-4). These observations eventually led to an increased understanding of the concept of genomic imprinting. Both conditions are currently diagnosed in the clinical setting using FISH techniques to identify the deleted region or DNA methylation studies that can discriminate between the genes inherited from mother and father. Table 176-1includes the other microdeletion syndromes (ie, 22q11 deletion syndrome, trichorhinophalangeal syndrome, and Williams syndrome).

FIGURE 174-4. A 6-year-old girl with the 22q11 deletion syndrome, illustrating the distinctive tall nasal root and bridge with a bulbous nasal tip and a small mouth. (Source: Modified from Jorde LB, Carey JC, Bamshad MJ, White RL. Medical Genetics. St. Louis, MO: Mosby; 2006.)

One microdeletion syndrome that warrants expanded discussion is the 22q11 deletion syndrome, which is a fascinating account of how technological advances helped explain seemingly disparate but previously recognized entities.^13,14 The 22q11 deletion syndrome has been referred to by many different eponyms and labels, and this has led to considerable confusion. In the past, the 22q11 deletion syndrome was referred to as the DiGeorge syndrome; Sprintzen syndrome; velocardiofacial syndrome; or cleft palate, absent thymus, congenital heart disease (CATCH 22 is also a term, but has been rejected by parent support groups). All these labels have some merits but also considerable disadvantages. Thus, this condition is most properly referred to as the 22q11 deletion syndrome.

Estimates of frequency of 22q11 deletion syndrome suggest that it occurs in about 1 of every 4000 to 5000 infants. Indeed, the 22q11 deletion syndrome is responsible for a substantial percentage of newborns with conotruncal heart malformations (eg, about 30% of infants with truncus arteriosus have a 22q11 deletion).¹³ However, a deletion of chromosome 22q11 produces an extremely variable syndrome.

The 22q11 deletion syndrome phenotype consistently includes a characteristic craniofacial appearance (Fig. 174-4), but this finding is particularly subtle in the newborn. By 6 to 12 months the facial features are usually recognizable, although they are not distinctive. The majority of patients have some T-cell dysfunction and are occasionally labeled as having the DiGeorge “syndrome.” However, this T-cell dysfunction does not usually cause immune problems and is not a specific etiologic entity but an anomaly of pharyngeal development that is observed in many different conditions, although the most common cause is 22q11 deletion syndrome. Cleft palate or, more commonly, velopharyngeal insufficiency is observed in the majority of patients with 22q11 deletion syndrome. Learning disabilities are common in older children, but mental retardation is uncommon and not to be expected. A national support and foundation offer a number of valuable resources for the families of children with 22q11 deletion syndrome (www.ggc.org/ucfsup.html).

The microdeletion of chromosome 22q11 is sometimes visible on a routine karyotype. However, the diagnosis is confirmed most commonly using FISH to detect the absence of genes in the region deleted in most patients. Because of the heart defects observed in children with 22q11 deletion syndrome, all children with a conotruncal heart defect should be tested for the 22q11 deletion.

With the advent of subtelomeric FISH previously undelineated syndromes were recognized and characterized over recent years. The most important and common of these is the 1p36 deletion syndrome. This syndrome is likely the second most common deletion syndrome in humans and likely the most frequent terminal deletion syndrome. The pattern of malformation consists of intellectual disability, growth delays, microcephaly, seizures, a characteristic facial phenotype and heart defects, most importantly, a cardiomyopathy. The developmental disability is notable, and most children have significant language delays. The frequency of this condition among children with developmental delay supports the current strategy of performing CGH microarray in such children (see sections on developmental delays in Chapter 185).

OTHER ANEUSOMY SYNDROMES

Other important chromosome syndromes include those caused by deletions of 9p and 13q.¹ More than a hundred cases of each of these conditions have been reported and thus their clinical characteristics are well described. The 13q deletion syndrome is of particular importance, because children with deletions involving the q14 band are predisposed to the development of a retinoblastoma.

The most common partial trisomy syndromes involve trisomy of the 4p, 5p, and 9p. Patients with these less common aneusomy syndromes present with multiple congenital anomalies or developmental delay. As in the case of all aneusomy syndromes, the phenotypes of children affected with these conditions are relatively well delineated (see Table 176-1). In all cases of partial monosomy or trisomy, parental karyotypes should be performed to look for associated structural rearrangements that may predispose to a partial monosomy or trisomy. Consequently, the recurrence risk in these situations depends on parental karyotype.

It is beyond the scope of this chapter to describe the many uncommon chromosome syndromes associated with partial deletion or duplication of a chromosome. Clinical pheno-types have been associated with partial monosomy or trisomy of some portion of the long and short arms of every chromosome. The phenotypes associated with these chromosomal abnormalities are highly variable and hard to define because of the varying types of chromosome duplications and deficiencies. For example, several different phenotypes have been associated with deletions of different segments of chromosome 1. Of note in recent years, the 1p36 deletion syndrome, primarily delineated when subtelomeric FISH became a common diagnostic tool, has been acknowledged as a recognizable and important cause of intellectual disability.¹⁵

SEX CHROMOSOME ABNORMALITIES

About 1 in 500 live-born infants has an abnormality of the X or Y chromosomes. Three conditions—47, XXY (Klinefelter syndrome), 47, XYY, and 47, XXX—comprise over 80% of this group of disorders. The phenotypic characteristics of these conditions are more subtle typically than those caused by abnormalities of the autosomes. Therefore, the diagnosis is not entertained unless there is a high index of suspicion. The phenotypes of children with Turner syndrome, 49, XXXXY, and 49, XXXXX, are more distinct.^1,3 Klinefelter syndrome is discussed in Chapter 173.

Turner syndrome was described in 1938 by Henry Turner in females with proportionate short stature, a lack of secondary sexual characteristics, and gonadal dysgenesis leading to infertility.¹⁶ Many patients with Turner syndrome also have congenital heart defects, most commonly obstructive lesions of the left side of the heart (bicuspid aortic valve in 50% and coarctation of the aorta in 15–20%). These abnormalities are the cause of the most significant medical problems in girls with Turner syndrome. However, affected individuals also have a characteristic physical appearance consisting of a triangular shaped face, posteriorly rotated ears, a broad neck, and lymphedema of the hands and feet at birth.

The prevalence of Turner syndrome is low compared with other sex chromosome abnormalities, with about 1/2500 to 1/5000 live-born females having the condition. If no heart abnormalities are present, the primary medical impact of the syndrome is the short stature and the associated infertility and lack of secondary sexual development. In many cases of newborn females with Turner syndrome, the phenotype is easily recognizable and diagnosed on clinical features alone. However, the range of abnormalities observed in children with Turner syndrome is much wider than many of the chromosome syndromes. Clues such as dorsal lymphedema, the presence of a left-sided obstructive cardiac lesion, or a webbed neck suggest ordering a karyotype. Guidelines for the routine medical care and health supervision of girls with Turner syndrome have been developed by the American Academy of Pediatrics.¹⁷ Various support groups for families have been established (www.turner-syndrome-us.org/).

About half of all females with the Turner syndrome phenotype will have the 45, X chromosome constitution. The remaining cases will have either 45,X/46,XX mosaicism or some degree of monosomy of the X short arm. There is a long listing of various karyotypic findings associated with the Turner syndrome phenotype.

In addition to the clinical settings mentioned above, the 45,X karyotype will also be seen in the evaluation of fetal loss; more than 90% of all conceptions with 45,X die before birth. The characteristic fetal loss occurs in the second trimester with massive hydrops and a nuchal bleb (cystic hygroma). The hy-drops and nuchal bleb are related to a malformation of lymph channel development that is probably also responsible for the web neck in live-born females with Turner syndrome.

Other than the common autosomy-trisomy syndromes and the Turner syndrome, knowledge of the natural history of most human chromosome disorders is generally lacking. There are no multicenter studies that describe the occurrence of manifestations over time, and there is little information on children beyond infancy and early childhood.

CHROMOSOMAL INSTABILITY SYNDROMES

A number of autosomal recessive conditions exhibit an increased occurrence of chromosome breaks under specific laboratory conditions. These disorders are termed chromosome instability syndromes and include ataxia-telangiectasia (see Chapter 188), Bloom syndrome, Fanconi anemia, and xeroderma pigmentosum (see Table 176-1). Among patients with Fanconi anemia, the frequency of breaks can be increased further when the chromosomes are exposed to certain alkylating agents. Patients with Bloom syndrome have a high incidence of somatic cell sister chromatid exchange. All these syndromes are associated with a significant risk for cancer (for more information, see Chapter 443).

Substantial progress has been made in understanding the etiology of these conditions. All the chromosome instability syndromes are thought to be the result of faulty DNA replication or repair, although only in the past decade have the genes responsible for these conditions been identified.