++
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
++
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,7 and 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 Robertsonian 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.org and 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.
++
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
++
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).
++
++
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 Angelman 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 176-1 includes the other microdeletion syndromes (ie, 22q11
deletion syndrome, trichorhinophalangeal syndrome, and Williams
syndrome).
++
++
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 phenotypes 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