Chromosomal Syndromes Introductory article

and Genetic Disease . Introduction

Article Contents

Frederick W Luthardt, Swedish Hospital Medical Center, Seattle, Washington, USA . Chromosome Abnormalities

Elisabeth Keitges, Dynacare Northwest, Seattle, Washington, USA . Outline of Chromosome Syndromes
. Maternal Age Effects
. Recurrence Risks
The normal human chromosome complement consists of 46 chromosomes comprising 22
. Summary
morphologically different pairs of autosomes and one pair of sex chromosomes. Variation
in either chromosome number or structure frequently results in significant mental
and/or clinical abnormalities. Chromosomal syndromes are associated with specific
chromosomal abnormalities.

Introduction Figure 1 (Down syndrome karyotype with trisomy 21), or to

With the discovery in 1956 that the correct chromosome
number in humans is 46, the new era of clinical cytogenetics
began its rapid growth. During the next few years, several
major chromosomal syndromes with altered numbers of
chromosomes were reported, i.e. Down syndrome (trisomy
21), Turner syndrome (45,X) and Klinefelter syndrome
(47,XXY). Since then it has been well established that
chromosome abnormalities contribute signicantly to
genetic disease resulting in reproductive loss, infertility,
stillbirths, congenital anomalies, abnormal sexual devel-
opment, mental retardation and pathogenesis of malig-
nancy. Specic chromosome abnormalities have been
associated with over 60 identiable syndromes. They are
present in at least 50% of spontaneous abortions, 6% of
stillbirths, about 5% of couples with two or more
miscarriages and approximately 0.5% of newborns. In
women aged 35 or over, chromosome abnormalities are
detected in about 2% of all pregnancies. Some of the
abnormalities and their clinical consequences will be
discussed in the following sections.
the absence of a single chromosome, or monosomy, as seen
in Figure 2 (Turner syndrome karyotype with 45,X).
The most common clinically signicant chromosome
abnormalities involving aneuploidy are frequently de-
tected in newborns (Table 1). Although autosomal and sex
chromosome trisomies result in clinical abnormalities they
are more viable than monosomies, with the exception of
monosomy X (45,X Turner syndrome). However, fewer
than 5% of 45,X conceptions actually survive to birth.
Aneuploidy is frequently associated with maternal age and
constitutes a signicant portion of chromosome abnorm-
alities observed in spontaneous abortions (Table 2) and
detected prenatally in fetuses (Table 3).
Polyploidy resulting from triploidy (69 chromosomes)
or tetraploidy (92 chromosomes) are lethal conditions
most frequently seen in spontaneous abortions and very

Chromosome Abnormalities
Numerical abnormalities
Chromosome abnormalities are classied as either numer-
ical or structural and may involve more than one
chromosome. In discussing numerical abnormalities,
certain terms need to be claried. The normal human
chromosome complement consists of 46 chromosomes
(diploid) which is double the euploid (haploid) or gamete
complement of 23. Exact multiples of euploid chromosome
sets are either diploid or polyploid, i.e. triploid or
tetraploid consisting of three or four euploid sets,
respectively. Aneuploidy refers to the presence of an extra Figure 1 47,XX, 1 21 female Down syndrome karyotype demonstrating
copy of a specic chromosome, or trisomy, as seen in trisomy 21. (Karyotype prepared by Dave McDonald.)

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 Chromosomal Syndromes and Genetic Disease

Table 1 Incidence of chromosomal abnormalities in newborns

Type of abnormality Approximate incidence
Sex chromosome abnormalities in males
47,XXY 1/1080 male births
47,XYY 1/1080
Other 1/1350
Total 1/385
Sex chromosome abnormalities in females
45,X 1/9600 female births
47,XXX 1/960
Other 1/2740
Total 1/660
Autosomal numerical abnormalities in infants
Trisomy 21 1/800 live births
Trisomy 18 1/8140
Trisomy 13 1/19 000
Triploidy 1/57 000
Total 1/695

Figure 2 45,X Turner syndrome karyotype demonstrating monosomy X. Structural abnormalities in infants (autosomes and sex
(Karyotype prepared by Dave McDonald.) chromosomes)
Balanced rearrangements
rarely in newborns with a short survival time. Triploidy is
Robertsonian 1/1120 live births
more common and is related to abnormal events prior to or Other 1/965
during fertilization: most often triploidy results from two Unbalanced rearrangements 1/1675
haploid sperm fertilizing a single haploid egg. Total 1/395
Aneuploid and normal diploid cells can occasionally
exist simultaneously in an individual. This condition is All chromosome abnormalities 1/160 live births
known as mosaicism and involves two or more distinct cell (autosomes and sex chromosomes)
populations derived from a single zygote or fertilized egg. Modified from Thompson et al. (1991) Genetics in Medicine, 5th edn.
Mosaicism can involve either autosomal or sex chromo- WB Saunders.
somes but most frequently involves sex chromosomes.
Mosaicism is seen in approximately 0.2% of fetuses
prenatally, 1% of Down syndrome patients, 10% of
Klinefelter syndrome patients and over 30% of patients Table 2 Relative frequencies of dierent abnormalities in
with Turner syndrome. The clinical signicance of mosai- chromosomally abnormal spontaneous abortions
cism depends upon the proportion and tissue distribution Abnormality Percentage
of the aneuploid cells. Chimaerism, in contrast, is
distinguished from mosaicism in that the dierent cell Trisomies 52
lines are derived from more than one zygote. 45,X 18
Triploidy 17
Translocations 24
Structural abnormalities Modied from Harper (1988) Practical Genetic Counselling, 3rd edn.
Wright.
Structural rearrangements frequently alter chromosome
morphology. Chromosome morphology is based upon
location of the centromere or primary constriction that
divides a chromosome into a short arm p and a long arm consists of two identical sister chromatids joined at the
q (Figure 3a). Chromosomes are metacentric when the centromere. Chromosomes normally have one centromere.
centromere is in the middle with short and long arms of A dicentric chromosome has two centromeres (Figure 3l)
roughly equal length (Figure 3i), submetacentric when the and an acentric chromosome has none. At metaphase,
centromere is closer to one end with short and long arms of when chromosomes are typically examined, sister chro-
unequal length (Figure 3a), and acrocentric when the matids appear fused as a result of the staining method
centromere is near one end with very small short arms necessary to produce the banding patterns essential for
(Figure 3l). The centromere is essential for correct segrega- chromosome identication (Figures 1 and 2). Each band
tion of chromosomes during cell division. DNA replication and subband has an assigned designation that identies the
prior to cell division ensures that each chromosome chromosome arm, region and specic number as published

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 Chromosomal Syndromes and Genetic Disease

Figure 3 Chromosome structural rearrangements, described in the text. (a) Chromosome arm and numerical banding designations according to
ISCN (1995). (b) Terminal deletion and (c) interstitial deletion, each with loss of acentric fragment. (d) Pericentric inversion and (e) paracentric
inversion, each with rotation of segment between breaks. (f) Direct duplication and (g) inverted duplication. (h) Isochromosome generation for short and
long arms. (i) Ring chromosome with two acentric fragments. (j) Insertion of segment from one chromosome into a nonhomologous chromosome.
(k) Reciprocal translocation with exchange of segments between nonhomologous chromosomes. (l) Robertsonian translocation between two
acrocentric chromosomes. (Illustration prepared by Dave McDonald.)

by the 1995 International System for Human Cytogenetic
Nomenclature (Figure 3a). Banding patterns are necessary
to identify specic structural rearrangements within or
between dierent chromosomes.
Structural rearrangements involve chromosome break-
age and reunion within a single chromosome or between
two or more dierent chromosomes resulting in either
balanced or unbalanced karyotypes. Rearrangements are
balanced if there is no net change in chromosome material
or unbalanced if there is either a gain (partial trisomy) or
loss (partial monosomy) of chromosome material.
The frequency of structural abnormalities varies con-
siderably in dierent populations. The highest frequency is
in spontaneous abortions and the lowest in newborns
(Table 4). This reduction can, in part, be explained by fetal
losses prior to birth, particularly in those cases with
signicant unbalanced rearrangements.

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 Chromosomal Syndromes and Genetic Disease
Table 3 Maternal age related frequency of aneuploid fetuses detected prenatally
Maternal age range (years) Total number of fetuses
3549 19 672
Modified from Schreinemachers et al. (1982) Human Genetics 61: 318324.
Table 4 Frequency of structural chromosome abnormalities in various populations
Structural Spontaneous
rearrangement abortions (%)
Balanced
24
Unbalanced
Data from various sources.
Unbalanced rearrangements
Unbalanced rearrangements usually result in signicant
clinical abnormalities due to loss, duplication or both (in
some cases) of genetic material. Some examples of
unbalanced rearrangements are deletions, duplications,
rings and isochromosomes (Figure 3).
Deletions result in loss of chromosome material from a
single chromosome. Terminal deletions result from a single
break within one chromosome arm with loss of material
distal to the break (Figure 3b). Interstitial deletions involve
two breaks within the same chromosome arm with loss of
the material between the breaks (Figure 3c). Ring chromo-
somes are formed by breaks occurring in each chromosome
arm with loss of material distal to the breaks and with
subsequent rejoining of the broken ends (Figure 3i). Ring
chromosomes vary in size depending upon how much
material has been lost. They are often unstable during cell
division and can, very rarely, be transmitted from parent to
ospring.
Duplication of a chromosome segment usually occurs by
unequal crossing over between homologous chromosomes
or sister chromatids (Figure 3f). Duplications can also result
from abnormal meiotic segregation in a translocation
(Figure 3k,l) or meiotic crossing over in an inversion
(Figure 3d,e) carrier. In general, duplications are less
harmful than deletions but they inevitably are associated
with some clinical abnormalities. The degree of clinical
severity is correlated with size of the duplicated segment.
An isochromosome is a chromosome consisting of two
identical copies of one arm and none of the other (Figure 3h).
In a person with 46 chromosomes, an isochromosome
results in partial monosomy and partial trisomy. Isochro-
mosomes most likely result from exchange between
homologues during meiosis, or from breakage and reunion
of sister chromatids near the centromere. Centromere
misdivision during meiosis II is also considered to be a
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Aneuploid rate per 1000
Trisomy 21 Trisomy 18 Trisomy 13 XXX XXY XYY
9.1 2.5 0.6 1.0 1.3 0.5
Prenatal
diagnosis (%) Newborn (%)
0.4 0.2
0.11 0.05
possible, though less likely, mechanism. The most common
isochromosome involves the long arm of the X-chromo-
some which is frequently seen in individuals with Turner
syndrome. Most X-isochromosomes are actually dicentric.
Inactivation of one centromere makes this abnormal
chromosome more stable during cell division. Autosomal
isochromosomes also occur and most frequently involve
acrocentric chromosomes with loss of their short arms.
Unbalanced isochromosomes are always associated with
clinical abnormalities owing to their inherent genetic
imbalance.
Balanced rearrangements
Carriers of balanced chromosomal rearrangements are
usually clinically normal if no essential chromosome
material is lost and no genes are damaged by the breakage
and reunion process. However, they can produce unba-
lanced gametes and have an increased risk for chromoso-
mally abnormal ospring. Balanced rearrangements
include inversions, insertions, reciprocal translocations
and Robertsonian translocations (Figure 3).
Inversions are rearrangements within a single chromo-
some resulting from two breaks with the intervening
segment being rotated 1808 prior to reconstitution.
Inversions are classied as either pericentric, which have
a single break in each arm (Figure 3d) or paracentric, which
have two breaks in one arm (Figure 3e). Pericentric
inversions frequently produce a change in the relative
arm lengths; paracentric inversions do not but can be
identied by changes in the banding pattern of the
chromosome arm aected. Inversion carriers are usually
clinically normal but may have an increased risk for
ospring with partial trisomy and monosomy. This is
because when chromosomes pair during meiosis an
inversion loop is formed when the inverted segment pairs
with its normal homologue and if an odd number of
crossovers occur, unbalanced recombinant chromosomes

are produced. Pericentric inversions can produce recombi-
nants with duplication and deciency of chromosome
segments. The viability of these recombinant products is
dependent upon the size of the unbalanced segments.
Recombinant chromosomes derived from paracentric
inversions are typically acentric or dicentric and usually
result in nonviable ospring since these chromosomes are
unstable during cell division.
Translocations result from the exchange of chromosome
segments between two or more nonhomologous chromo-
somes. There are three types of translocations: reciprocal,
Robertsonian and insertional. Reciprocal translocations
are produced by the exchange of broken-o segments
between two dierent chromosomes (Figure 3k). Carriers of
balanced reciprocal translocations are usually normal but
they have an increased risk for unbalanced ospring. The
actual risk is associated with segregation of the transloca-
tion components, position of breakpoints and centromere
location. In general, viability is correlated with size of the
unbalanced segment. Robertsonian translocations involve
two acrocentric chromosomes that join near their centro-
meres, to form a single chromosome (Figure 3l). Frequently,
this single chromosome has two centromeres, resulting in a
dicentric chromosome. Balanced Robertsonian transloca-
tion carriers have only 45 chromosomes including the
dicentric chromosome. Carriers of balanced Robertsonian
translocations are usually clinically normal but have an
increased risk of unbalanced ospring. This risk is higher
for female carriers since males frequently have infertility
problems. An insertional translocation is the result of three
breaks such that a nonreciprocal change occurs when the
segment from one chromosome is inserted into another
chromosome (Figure 3j). Insertions are relatively rare since
they involve three breaks. Insertion carriers are clinically
normal but have an increased risk for ospring with partial
monosomy or partial trisomy for the inserted segment.
Outline of Chromosome Syndromes
Common autosomal trisomies
Trisomy 21 (Down syndrome) is one of the best-recognized
and most common chromosome disorders. It is the single
most common genetic cause for mental retardation. The
incidence of Down syndrome is approximately 1/800
newborns. The risk for having a child with trisomy 21
Down syndrome increases with maternal age. Clinical
features include mental and growth retardation, charac-
teristic facies and other abnormalities described in Table 5.
Approximately 94% of Down syndrome patients have
trisomy 21 (Figure 1) resulting from meiotic nondisjunction,
the failure of homologous chromosomes or sister chroma-
tids to separate during cell division. In about 95% of cases
the extra chromosome 21 is of maternal origin, and of these
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Chromosomal Syndromes and Genetic Disease
cases approximately 80% are due to an error during
meiosis I. About 4% of Down syndrome patients have an
unbalanced Robertsonian translocation involving chro-
mosome 21. Approximately 60% of these translocations
involve the long arm of chromosome 13, 14, or 15 (most
frequently chromosome 14). About half of these transloca-
tions are de novo and half are inherited from a balanced
carrier parent (usually the mother). Nearly 40% of
unbalanced Robertsonian translocations involve only
chromosomes 21 and 22. Most of these (
90%) involve
21/21 long-arm fusions or isochromosomes and nearly all
are de novo. The rare parent who is a balanced 21/21
isochromosome carrier has a 100% risk for having a viable
ospring with Down syndrome. Female carriers of
balanced 14/21 or 21/22 Robertsonian translocations have
a 1015% risk for an unbalanced Down syndrome child.
Male carriers have a risk of less than 5%. Mosaicism
involving a mixture of normal diploid cells and trisomy 21
cells is present in about 2% of Down syndrome patients.
Trisomy 18 (Edwards syndrome) is the second most
common autosomal trisomy syndrome. It has a frequency
of about 1 in 8000 live births. Clinical features include
failure to thrive, cardiac and kidney problems and other
congenital abnormalities (Table 5). Postnatal survival is
poor and more than 90% die within the rst 6 months.
About 80% are female. The incidence of trisomy 18
increases with maternal age. Very few cases of trisomy 18
mosaicism have been reported. Many features character-
istic of trisomy 18 have also been reported in patients with
unbalanced translocations involving all or most of
chromosome 18 long arm. Based upon limited data, the
recurrence risk for trisomy 18 is approximately 1%.
Trisomy 13 (Patau syndrome) is the least common of the
major autosomal trisomies with an estimated incidence of 1
in 20 000 live births. Owing to severe clinical abnormalities
including central nervous system malformations, heart
defects, growth retardation and numerous other congeni-
tal anomalies (Table 5), trisomy 13 patients rarely survive
the newborn period. Trisomy 13 is associated with
advanced maternal age. The extra 13 usually results from
a maternal meiotic nondisjunctional error. About 20% of
cases have an unbalanced Robertsonian translocation
involving chromosome 13. Balanced 13/14 Robertsonian
translocation carriers have less than 2% risk of having an
unbalanced trisomy 13 ospring. Trisomy 13 mosaicism is
rare and may be associated with less severe clinical
anomalies.
Common sex chromosome abnormalities
Sex chromosome abnormalities have less severe clinical
anomalies than those associated with comparable auto-
somal imbalances. This dierence can be attributed to
genetic inactivation of all but one X-chromosome in those
cases where multiple copies are present, and the relatively
5
 Chromosomal Syndromes and Genetic Disease

Table 5 Clinical features of patients with common autosomal or sex chromosome aneuploidy
Syndrome Karyotype Main clinical features
Down Trisomy 21 Short, broad hands with single palmar crease, decreased muscle tone, mental
retardation, broad head with characteristic features, open mouth with large tongue,
up-slanting eyes
Edwards Trisomy 18 Multiple congenital malformations of many organs, low-set malformed ears, receding
mandible, small eyes, mouth and nose with general eln appearance, severe mental
deciency, congenital heart defects, horseshoe or double kidney, short sternum,
posterior heel prominence
Patau Trisomy 13 Severe mental deciency, small eyes, cleft lip and/or palate, extra ngers and toes,
cardiac anomalies, midline brain anomalies, genitourinary abnormalities
Turner 45,X Female with retarded sexual development, usually sterile, short stature, webbing of skin
in neck region, cardiovascular abnormalities, hearing impairment, normal intelligence
Klinefelter 47,XXY Male, infertile with small testes, may have some breast development, tall, mild mental
deciency, long limbs, at risk for educational problems
Triple X 47,XXX Female with normal genitalia and fertility, at risk for educational and emotional
problems, early menopause
XXY 47,XYY Tall male with normal physical/sexual development, normal intelligence, increased
tendency for behavioural and psychological problems
Data from various sources.

low gene content of the Y-chromosome. Sex chromosome
aneuploidy is relatively common, with overall frequency of
about 1 in 500 live births (Table 1). Some (XXX, XXY,
XYY) are relatively frequent in newborns but rare in
spontaneous abortions. Monosomy X (Turner syndrome),
in contrast, is one of the most common chromosome
abnormalities seen in spontaneous abortions but relatively
rare in newborns.
Turner syndrome (45,X)
The frequency of Turner syndrome is about 1 in 8000
newborn females. Clinical features in newborns often
include webbed neck, low hairline, puy hands and feet,
wide spaced nipples and cardiovascular problems. Later in
life, these girls are typically short, sexually immature and
infertile (Table 5). Slightly more than 50% of Turner
syndrome patients have a 45,X karyotype (Figure 2). The
remaining Turner patients have other sex chromosome
abnormalities of the X-chromosome involving isochromo-
somes, short-arm deletions and rings. About 30% of
Turner patients are mosaics consisting of 45,X cells plus
other cells with two or more normal X-chromosomes,
structurally abnormal X-chromosomes or a Y-chromo-
some.
Approximately 9599% of 45,X conceptions fail to
survive to term and account for about 18% of chromoso-
mally abnormal spontaneous abortions. The incidence of
45,X is not associated with maternal age. The paternal X-
chromosome is missing in about 75% of 45,X patients.
Klinefelter syndrome (47,XXY)
Klinefelter syndrome has a frequency of about 1 in 1000
newborn males (Table 1). Unlike Turner syndrome, males
with Klinefelter syndrome are not usually detected in the
newborn period. These individuals are generally normal in
appearance before puberty. After puberty they are
frequently ascertained in infertility clinics or identied by
their small testes, breast enlargement and tall stature
(Table 5). Signicant mental retardation is not part of this
syndrome but patients have a higher incidence of educa-
tional and emotional problems. Most Klinefelter patients
have a 47,XXY karyotype. At least 10% have mosaicism
involving normal 46,XY cells plus another population of
cells with two or more X chromosomes. Mosaic patients
have more variable clinical features and occasionally may
have relatively normal testicular development.
Cytogenetic and molecular data have indicated that
47,XXY is equally likely to result from a maternal or
paternal meiotic nondisjunctional error. Maternally de-
rived cases are associated with maternal age. Variants of
Klinefelter syndrome include those patients with more
than two X-chromosomes, multiple X-chromosome mo-
saicism and multiple Y-chromosomes. The presence of
additional X-chromosomes (more than two) is associated
with increasing severity of clinical abnormalities including
mental retardation, sexual development and skeletal
anomalies.
47,XYY syndrome
Approximately 1 in 1000 newborn males have a 47,XYY
karyotype (Table 1). XYY males have no discernible clinical

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 Chromosomal Syndromes and Genetic Disease

features at birth or in infancy. Their mental and physical
development is normal and they are fertile (Table 5).
Although most 47,XYY patients are clinically normal,
they tend to be taller than normal and have an increased
tendency for behavioural and learning problems as
children and young adults. Y-chromosome aneuploidy
results from paternal meiotic nondisjunction and is not
associated with maternal age.
Trisomy X syndrome (47,XXX)
The frequency of 47,XXX in newborn females is about 1 in
1000 (Table 1) and is associated with maternal age. Most
XXX females are clinically normal with normal gonadal
function and fertility. However, there is an increased risk
for learning disabilities, reduction in performance IQ,
menstrual problems and early menopause (Table 5). Fe-
males with more than three X-chromosomes (XXXX and
XXXXX) have been reported but, in comparison to
47,XXX, are quite rare. These tetra-X and penta-X females
are all mentally retarded and have more severe clinical
problems.
Autosomal deletion and duplication
syndromes
Identication of common autosomal deletions requires
precise chromosomal localization of the missing segment.
Chromosome banding patterns make this localization
possible if the deletion is cytogenetically visible. Detection
of common deletions and also very small deletions not
visible by routine cytogenetic analysis (microdeletions) has
been made possible by uorescence in situ hybridization
(FISH) technology. This technique involves hybridizing
specic uorescently tagged DNA probes to metaphase
chromosomes, which are detectable by UV excitation.
Absence of a locus-specic uorescent probe from one
homologue is indicative of a microdeletion.
Several common autosomal deletion syndromes are
described in Table 6. The critical region for WolfHirsch-
horn syndrome has been assigned to 4p16.3. In 90% of
cases the deletion is de novo and in 10% it is inherited as an
unbalanced translocation. The deletion is usually visible
cytogenetically, but occasionally it is too small and can
only be identied molecularly with specic DNA probes
utilizing FISH methods. Cri du chat syndrome is one of the
earliest deletion syndromes to be described. It has an
incidence of about 1 in 50 000 births. The critical region has
been mapped to 5p15.2. About 90% of deletions are de
novo and 10% are derived from an unbalanced familial
translocation. LangerGiedion syndrome is a rare condi-
tion with microcephaly and mental retardation. The
critical region has been assigned to 8q24.11-q24.13. A
cytogenetically visible deletion is seen in about 50% of
cases.
More recently, a group of autosomal microdeletions or
contiguous gene syndromes have been identied that have
a consistent but complex phenotype associated with a very
small (usually 5 5 Mb) chromosomal deletion. Although
some microdeletions are cytogenetically visible, the current
method is to identify these syndromes by FISH utilizing
uorescently labelled DNA probes specic for the deleted
segments. Some of the more common microdeletion
syndromes are described in Table 7. In Williams syndrome
about 96% of patients have a deletion for the elastin gene,
which produces a protein necessary for elasticity of large
blood vessels, skin and other organs. The de novo deletion
is of maternal origin in 61% of cases and paternal in 39%.
Genomic imprinting, the dierential expression of alleles
depending on the parent of origin, has been reported for
the maternal deletion group of Williams patients since they
had signicantly more severe growth retardation and
microcephaly than the paternal deletion group. Some
genes mapped to the WAGR critical region have also
revealed genomic imprinting. The incidence for Prader
Willi syndrome and Angelman syndrome is approximately
1 in 10 000 births, respectively. About 60% of PraderWilli
and Angelman syndrome patients have a cytogenetically
visible deletion in the same region of chromosome 15.
FISH analysis identies a microdeletion in about 70% of
cases of both syndromes. DNA polymorphism demon-
strated that in PraderWilli syndrome the deleted 15 was of
paternal origin and was of maternal origin in Angelman
syndrome patients. These observations suggested that the
dierence in clinical features for patients with identical

Table 6 Common autosomal deletions

Syndrome Chromosome region deleted Main clinical features
WolfHirschhorn 4p16.3 Severe growth retardation, midline facial defects, mental retardation,
small head, prominent frontal bone between eyebrows, cleft lip/
palate, cardiac defects, wide-spaced eyes, broad nasal bridge
Cri du chat 5p15.2 High-pitched cry, wide-spaced eyes, small chin, small head, round face,
severe psychomotor and mental retardation
LangerGiedion 8q24.11-q24.13 Small head, mental retardation, sparse hair, bulbous nose, short
stature, multiple cartilaginous growths on bone surfaces
Data from various sources.

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 Chromosomal Syndromes and Genetic Disease

deletions implies dierential expression depending upon
parental origin (genomic imprinting). About 30% of
PraderWilli patients have two copies of maternal
chromosome 15 and no paternal copy, a condition called
uniparental disomy (UPD). Fewer than 5% of Angelman
patients have paternal UPD for chromosome 15. A small
proportion (1% PraderWilli and 4% Angelman) have
neither deletions nor UPD but have abnormal methylation
patterns (dierential expression of imprinted genes) at loci
in 15q11-q13 due to imprinting mutations. At least 20% of
nondeletion, non-UPD 15, normally methylated and
cytogenetically normal Angelman patients have other
genetic mutations. A visible cytogenetic deletion is seen
in about 50% of MillerDieker syndrome patients. FISH
analysis identies a microdeletion in 90% of all Miller
Dieker patients. Hemizygosity for an interstitial deletion of
chromosome 22q11.2 is associated with variable but
overlapping syndromes known as Catch 22, DiGeorge
syndrome and velocardiofacial syndrome. As a group,
these syndromes have an incidence of about 1 in 5000 births
and may account for 5% of all congenital heart defects.
Cytogenetic deletions are seen in about 30% of these
patients. FISH analysis is much more sensitive and
identies 8590% of patients with microdeletions.
Autosomal duplication syndromes are much less com-
mon than autosomal deletion syndromes. Several auto-
somal duplication syndromes are described in Table 8.
BeckwithWiedeman syndrome has an incidence of 1 in
13 700 births. Approximately 85% are de novo and 20
28% of these cases are due to paternal UPD for region
11p15.5. Fifteen per cent of cases are familial, due to
maternal carriers with translocations or inversions with a
breakpoint on 11p. These female carriers are clinically
normal but their ospring may have clinical eects
suggesting a role for genomic imprinting. Cytogenetic
abnormalities are present in 23% of BeckwithWiede-
man patients. The most frequent abnormality is duplica-
tion of 11p13!p15 resulting from the unbalanced
segregation of a paternal translocation or inversion. De
novo 11p15.5 duplications of paternal origin have also been
reported in some patients with BeckwithWiedeman
syndrome. Patients with duplication or trisomy for
11p15.5 have a higher incidence of clinical abnormalities
than those with normal chromosomes. CharcotMarie
Tooth disease type 1A (CMT1A) is the most common
inherited peripheral neuropathy in humans and has a
prevalence rate of 1 in 2500. In most cases CMT1A patients
have normal chromosomes with duplication of DNA
markers within 17p11.2!p12. A number of CMT1A
patients have been reported with cytogenetically visible
duplication of 17p11.2p12, demonstrating that this syn-
drome is correlated with a gene dosage eect for this
chromosome region. Misalignment of homologous chro-
mosomes resulting in unequal crossing over between non-
sister chromatids during meiosis is the most likely
mechanism for this type of de novo chromosome duplica-
tion. Cat-eye syndrome results from duplication of the
proximal portion of the chromosome 22 long arm. The
most common form of this duplication is a supernumerary
(extra) dicentric bisatellited chromosome 22 designated as

Table 7 Autosomal microdeletion syndromes

Chromosome
Syndrome region Incidence Main clinical features
Williams 7q11.23 1/20 000 Cardiac anomalies, mental retardation, characteristic facies, growth
retardation, gregarious disposition, connective-tissue problems
WAGR 11p13 Kidney tumour, absence of iris, genital abnormalities, growth retardation
PraderWilli 15q11.2 1/10 000 Developmental delay, mental retardation, decreased muscle tone, obesity,
small genitals, excessive appetite, hypopigmentation
Angelman 15q11.2 1/10 000 Developmental delay, mental retardation, unstable gait, absence of speech,
hyperactivity, spontaneous laughter, hypopigmentation
MillerDieker 17p13.3 Smooth brain, small head, small chin, growth failure, cardiac abnormalities
SmithMagenis 17p11.2 1/25 000 Flat midface, wide head, broad nasal bridge, short ngers and toes, mental
retardation, hyperactivity, short stature, characteristic behavioural
problems
Alagille 20p11.23-p12.2 Chronic bile ow suppression, dysmorphic facies, ring-like corneal opacity,
vertebral arch defects, narrowing of heart opening
Catch 22 22q11.2 Cardiac defects, abnormal facies, underdeveloped thymus, cleft palate,
decreased calcium in blood
DiGeorge 22q11.2 1/5000 Underdeveloped thymus and parathyroid glands, facial abnormalities,
cardiac defects
Velocardiofacial 22q11.2 Cleft palate, abnormal nose, developmental delay, cardiac abnormalities
Data from various sources.

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 Chromosomal Syndromes and Genetic Disease

Table 8 Autosomal duplication syndromes

Chromosome
Syndrome region duplicated Main clinical features
BeckwithWiedemann 11p15.5 Large tongue, tissue and organ overgrowth, mild mental retardation
CharcotMarieTooth 17p11.2-p12 Decreased reexes, progressive distal muscular wasting, decreased
disease type 1A muscle tone, sensory neuropathy
Cat-eye 22pter-q11.2 Eye defects, absence of anal opening, skin tags in front of ears,
characteristic facies, renal, skeletal and genital anomalies, mental
retardation
Data from various sources.

inv dup(22)(q11.2). This inverted duplication process
requires breakage at 22q11.2 in each of two sister or non-
sister chromatids and produces a chromosome containing
two copies of the cat-eye syndrome critical region
(CESCR) or a total of four copies for the patient. These
patients typically have 47 chromosomes owing to the
presence of the supernumerary inv dup(22)(q11.2).
Chromosome instability syndromes
There are several rare inherited syndromes characterized
by increased rates of spontaneous or induced chromoso-
mal breakage and predisposition to leukaemia and solid
cancers. The most extensively studied of these syndromes,
each caused by a dierent autosomal recessive gene, are
Bloom syndrome, Fanconi anaemia, ataxia telangiectasia
and xeroderma pigmentosum. These syndromes have
distinctive chromosome aberrations. Bloom syndrome is
characterized by quadriradial formations, which is the
exchange of chromatid segments between two chromo-
somes, and a high rate of sister chromatid exchange (SCE)
or exchanges between homologous chromosome segments.
Fanconi anaemia patients exhibit a high frequency of
chromosome breakage and nonhomologous chromosome
interchange following exposure to alkylating agents or
ultraviolet radiation. Their SCE rate is normal. Individuals
with ataxia telangiectasia show an increased level of
chromosome breaks and rearrangements and may have
abnormalities involving chromosome 14. These patients
have a normal SCE level. Patients with xeroderma
pigmentosum do not exhibit spontaneous chromosome
breakage; however, rearrangement, breaks, and increased
SCE rate are observed after exposure to ultraviolet
radiation.
Maternal Age Effects
Prenatal and live birth risks for trisomy 21 Down
syndrome are well established and are clearly associated
with maternal age (Table 9). In addition to trisomy 21, other
viable autosomal and sex chromosome aneuploidies, i.e.
trisomy 13, trisomy 18, XXX and XXY are also associated
with maternal age (Table 10).
Over 50% of chromosomally abnormal spontaneous
abortions are trisomic for various chromosomes and, as a
group, are more frequently associated with maternal age
when compared to polyploid and nontrisomic abortions.
Other chromosomally abnormal spontaneous abortions
with sex chromosome monosomy (45,X), triploidy, tetra-
ploidy and various other structural abnormalities are not
associated with maternal age.
The risk for aneuploidy increases with maternal age
primarily owing to meiotic nondisjunction errors asso-
ciated with reduced recombination or crossing over prior
to the rst meiotic division. This relationship has been
demonstrated in Down syndrome patients with trisomy 21.
Using DNA polymorphisms, the extra chromosome 21
was identied to be of maternal origin in over 90% of cases
and in approximately 80% of these cases nondisjunction
occurred during the rst meiotic division. A similar
relationship implicating a higher frequency of maternal
nondisjunction errors has also been reported for trisomy
13, 16, 18, XXX and XXY.
In addition to being associated with various aneuploid
syndromes, the maternal age eect has also been observed
in cases involving structural rearrangements associated
with nondisjunction and segregation errors. Data from
some balanced translocation carriers indicate that the risk
for unbalanced ospring due to 3:1 disjunction increases
with maternal age similarly to the risk pattern for trisomy
21. A maternal age eect has also been reported for some de
novo structural rearrangements, particularly those invol-
ving bisatellited supernumerary marker chromosomes.
In contrast to maternal age-related risk for aneuploidy,
younger women (less than 30 years of age) have an
increased recurrence risk for another trisomy 21 pregnancy
above what is normally expected for their age. In women
aged 30 or older, the recurrence risk for trisomy 21 is
similar to their age-related risk. The reason for the higher
recurrence risk in younger women is not known. In cases of
familial Robertsonian translocations involving chromo-
some 21, the risk for an unbalanced Robertsonian
translocation Down syndrome is higher for women less

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 Chromosomal Syndromes and Genetic Disease

Table 9 Maternal age incidence of Down syndrome in fetuses

its origin (de novo or familial) and the sex of the carrier
and liveborns patient. The empirical recurrence risk for trisomy 21 for
parents with normal chromosomes is approximately 1%
Incidence and increases to 2% if the mother is aged 40 or over. This
At amniocentesis indicates that in younger women the recurrence risk is
Maternal age (years) At birth (16 weeks) increased over what is expected for their age, while in
1519 1/1250 women 35 years or older the risk is age-related. With the
2024 1/1400 exception of trisomy 21, the recurrence risk for other
specic aneuploidy or polyploid conditions is rare.
2529 1/1100
Recurrence risk for unbalanced ospring of carriers with
30 1/900
various structural rearrangements has been derived
33 1/625 1/420 empirically (Table 11). Relatively specic risk estimates
34 1/500 1/325 are known for more common types of Robertsonian
35 1/350 1/250 translocations. The recurrence risk for an unbalanced
36 1/275 1/200 Robertsonian translocation Down syndrome child is
37 1/225 1/150 dependent upon which parent is the 14/21 or 21/22 carrier.
38 1/175 1/120 However, if a person is a 21/21 carrier, the recurrence risk is
39 1/140 1/100
100% regardless of which parent is the carrier. For carriers
of 13/14 Robertsonian translocation, the risk for an
40 1/100 1/75
unbalanced trisomy 13 ospring is 12%.
45 and over 1/25 1/20 Carriers of balanced rearrangements are usually clini-
Modified from Thompson et al. (1991) Genetics in Medicine, 5th edn. cally normal but have an increased risk for producing
WB Saunders. unbalanced ospring. Risk for unbalanced gametes or
segregation products depends upon location of chromo-
some breakpoints relative to the centromere and crossover
frequency. Since it is dicult theoretically to predict the
than 30 years of age than for those over 30. In this situation, rate of unbalanced ospring to be expected for any
lack of a maternal age eect can be attributed to knowledge particular structural rearrangement, risk estimates are
of being a translocation carrier and the impact of this based upon pooling of pregnancy outcome data from all
knowledge upon the decision to have more children. translocation or inversion carriers (Table 11).
More precise risk gures are available, however, for
carriers of t(11;22) translocations since this is probably the
most frequent reciprocal translocation found in humans.
Recurrence Risks This translocation is often familial, with reduced fertility in
males. Unbalanced probands are nearly always born to
Recurrence risks for chromosomal abnormalities depend
carrier females. The recurrence risk for the unbalanced
upon the type of abnormality, i.e. numerical or structural,

Table 10 Maternal age and chromosome abnormalities detected at amniocentesis

Rate per 1000
All chromosome
Age Trisomy 21 Trisomy 18 Trisomy 13 XXX XXY anomalies
35 3.9 0.5 0.2 0.6 0.5 8.7
36 5.0 0.7 0.3 0.7 0.6 10.1
37 6.4 1.0 0.4 0.7 0.8 12.2
38 8.1 1.4 0.5 0.8 1.1 14.8
39 10.4 2.0 0.8 1.2 1.4 18.4
40 13.3 2.8 1.1 1.5 1.8 23.0
41 16.9 3.9 1.5 1.8 2.4 29.0
42 21.6 5.5 2.1 2.4 3.1 29.0
45 44.2 18.0 7.0 62.0
Modified from Harper (1988) Practical Genetic Counselling, 3rd edn. Wright.

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 Chromosomal Syndromes and Genetic Disease

Table 11 Risks of unbalanced ospring for rearrangement rearrangement, the recurrence risk is generally considered
carriers to be negligible.

Percentage
of unbalanced
Type of rearrangement ospring
Summary
Robertsonian translocations Chromosome abnormalities contribute signicantly to
14/21, female 1015 genetic disease. This impact is seen in various human
14/21, male 25 populations in the eect on the fetus or individual directly
13/14, both sexes 12 or in the ability to produce healthy ospring. Autosomal
21/22, female 1015 abnormalities are generally more detrimental than sex
21/22, male 12 chromosome abnormalities. Abnormalities involving en-
21/21 both sexes 100 tire chromosomes or subtle microdeletions can result in
Reciprocal translocations clinically abnormal syndromes.
Pooled, both sexes 612
Ascertained by unbalanced child 20 Further Reading
Ascertained by unbalanced child with 50
small unbalanced segment de Grouchy J and Turleau C (1984) Clinical Atlas of Human
Chromosomes, 2nd edn. New York: Wiley.
Other ascertainment 25
Gelehrter TD, Collins FS and Ginsburg D (1998) Principles of Medical
t(11;22)(q23;q11.2) 57 Genetics, 2nd edn. Baltimore, MD: Williams and Wilkins.
Recurrence risk unbalanced t(11;22) 2 Harper PS (1988) Practical Genetic Counseling, 3rd edn. Boston, MA:
Wright.
Pericentric inversions
Hassold TJ (1986) Chromosome abnormalities in human reproductive
Ascertained by unbalanced child 510 wastage. Trends in Genetics 2: 105110.
Other ascertainment 2 Mitelman F (ed.) (1995) An International System for Human Cytogenetic
Nomenclature recommendations of the International Standing Commit-
Modied from Nora and Fraser (1993) Medical Genetics: Principles
and Practices, 4th edn. Lea and Febiger. tee on Human Cytogenetic Nomenclature, Memphis, Tennessee, USA,
October 913, 1994 Basel, Switzerland: Karger.
Nora JJ, Clarke Fraser F, Bear J, Greenberg CR, Patterson D and
Warburton D (1993) Medical Genetics: Principles and Practices, 4th
edn. Philadelphia: Lea and Febiger.
translocation is approximately 2%. It should also be
Schreinemachers DM, Cross PK and Hook EB (1982) Rates of trisomies
emphasized that the recurrence risk is substantially higher 21,18,13 and other chromosome abnormalities in about 20 000
if the parental rearrangement was originally ascertained prenatal studies compared with estimated rate in live births. Human
through a liveborn child with an unbalanced chromosome Genetics 61: 318324.
rearrangement, since this identies unbalanced chromo- Therman E and Sulsman M (1992) Human Chromosomes: Structure,
some complements that are compatible with survival to Behavior and Function, 3rd edn. New York: Springer.
term. In those cases involving a de novo structural Thompson MW, McInnis RR and Willard HF (1991) Genetics in
Medicine, 5th edn. Philadelphia: WB Saunders.

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