CHAPTER

43

Autosomal Trisomies
Cynthia J Curry
USCF Genetic Medicine Central California, Fresno, CA, USA

This article is a revision of the previous edition article by John L Tolmie and Una MacFadyen, volume 2, pp 10111037, 2007, Elsevier Ltd.

43.1 INTRODUCTION
It is now over 50 years since the recognition of the
chromosomal basis for trisomy 21 (T21), Down syndrome
(DS), first described clinically by the British physician John
Langdon Down in the nineteenth century. Recognition of
the other two major trisomies, trisomy 13 (T13) and trisomy 18 (T18), followed quickly after the discovery of T21
(1). Calculated live-birth rates of these conditions are 1 in
629 for T21, 1 in 6666 for T18, and 1 in 12,500 for T13
(2,3). The rates of all three autosomal trisomies increase
markedly with advancing maternal age (4,5,6) and are
lower than the rates observed in prenatal life since only
about 25% of T21 conceptions, 5% of T18 conceptions,
and 2.5% of T13 conceptions survive to birth, with most
but not all intrauterine deaths occurring in early pregnancy.
Postnatal mortality associated with T18 and T13 is
also very high, and the median survival time of infants
with these trisomies is about 10days. About 510% of
T18 and T13 infants survive to 1year of age (7,8,9).
These survival figures have not changed in recent years,
whereas T21 survival data indicate greatly improved
life expectancy. This is due primarily to the longer survival of infants with heart diseaseover 80% survival in
many centers (10,11). Survival has also increased because
of treatment of infections with antibiotics and generally
enhanced surveillance for the medical complications
of DS. This improved life expectancy has implications
for health care provision for older individuals with DS
(12,13) as well as informing decisions regarding health
maintenance and intervention in the infant and child
(14,15). In developed societies, increasing life expectancy
has been accompanied by a decreasing birth prevalence
of DS because of prenatal screening programs that offer
invasive and noninvasive prenatal diagnosis (3,16,17,18).

43.2 GENETIC COUNSELING

IN THE TRISOMIES
The diagnosis of an autosomal trisomy carries with it general issues, applicable in many cases, and specific or unique

issues in each individual case. From the geneticist and

genetic counselors perspective, there is no single approach
that is suitable for all who are affected by a trisomy. The
diagnosis of the affected fetus or infant is a fact that is
usually conveyed under difficult psychological circumstances. Parents need to be treated with respect and with
cultural sensitivity. Certainly the approach is different in
the prenatal setting versus the neonatal setting (19,20).
Parents should be intimately involved in all aspects
of this communication process and have consistently
reported that the words used when they are first informed
have a permanent effect on their later adjustments to their
new situation, their feelings about their child, and their
relationships with health professionals (21). In general,
since we can now anticipate a long lifespan for the child
with DS, optimism and encouragement seem warranted
and should be conveyed, especially when counseling the
family of a newborn (21,22).
Very early involvement of the clinical geneticist and
counselor are essential in the prenatal and postnatal
management of trisomies 13 and 18. It is critical to
assess the family unit in making management decisions
and to involve the parents fully. Variables such as family and financial resources, impact on siblings, and likely
burdens of care need to be compassionately explored
in making these decisions (23). Prenatal diagnosis by
amniocentesis or chorionic villus biopsy (and occasionally ultrasound only) can help a family reach appropriate
decisions about continuation of the pregnancy and management of labor and delivery, as well as decisions with
respect to the health care of their affected child. In trisomies 18 and 13, counseling should emphasize a realistic
appraisal of their childs prognosis, with an emphasis on
support and comfort care. In these two trisomies, heroic
measures such as intubation and cardiac surgery are usually not indicated because of the early lethality of these
conditions (8). Nonetheless, some families will request
intensive support of their newborn, and these decisions
need to be respectfully discussed by the health care team
and the family. Ongoing grief support is valuable and

2013, Elsevier Ltd. All rights reserved.

CHAPTER 43 Autosomal Trisomies

should be offered to these families who may suffer for

months or years after the loss of an affected child.
The Internet offers increasing accessibilty of information and support for families and many of these sites
offer easy connections to locally available services. Families with access to the Internet should be supported in
their efforts to seek outside information and geneticists
and counselors should act as facilitators in directing families to reputable sites. Sites such as those recommended
by the Medical Library Association or organizations
such as the National Institues of Health are reputable. A
consumer and patient health information section of the
Medical Library Association has a link that lists General
Health Websites You Can Trust. A list of the top 100
can be found at http://caphis.mlanet.org/consumer.
Many communities have excellent local resources
and support groups for parents of children with DS and
the National Down Syndrome Society also offers extensive information for families (http://www.ndss.org).
The Beyond the Basics patient information library is
open to all on the web and can be accessed through
a patient information Website (www.uptodate.com/
patients).
Families should be cautioned against sites offering
unorthodox treatment protocols or hopes for cures.
Families of affected children are uniquely vulnerable to
claims of treatment success and often may spend substantial amounts of money in the pursuit of an improved
developmental outcome. Counseling should address
these alternative therapies and help direct families to
legitimate sources of help.
The need for accurate information and authoritative
and consistent support for parents of children with trisomies 18 and 13 has led to several organizations such
as SOFT US (Support Organisation for Trisomies 18
and 13) and SOFT UK (www.soft.org). These groups
most often offer support and solace for those parents
of affected babies surviving the immediate neonatal
period; they also offer support for families whose
children have died.
In advising families, general principles of counseling
are always relevant. Many parents know of DS from
personal experience and seek to understand the range of
associations and the plans for specific investigation and
management at an early stage. An initial offer of basic
information leaflets with telephone or Internet contact
details, as well as details of a local parent support service, is appropriate.
Genetic counseling may be offered to the family at
one or several different stages: at the identification of
risk, at confirmation of diagnosis, or at the time of
another pregnancy for the parents or family planning
for the unaffected siblings. Each family will have different expectations of counseling and vastly different reactions to the information it brings (21,24). The counselor
who helps parents adjust to the diagnosis of an autosomal trisomy needs insight, intuition and compassion.

43.3 DOWN SYNDROME (TRISOMY 21)

43.3.1 Cytogenetic Diagnosis
In DS, no single clinical feature is pathognomonic,
although the combination of facial dysmorphic features
is highly specific (25). Chromosome analysis is necessary in each case to confirm the diagnosis and to assess
genetic implications for the family (26).
In 95% of DS cases there is a complete extra chromosome 21. This is most often due to a nondisjunction
event at the first meiotic division, and the chance of this
occurring rises in older mothers. In 4% of DS cases, the
extra chromosome 21 is translocated to or fused with
another large or small acrocentric chromosome (#13, 14,
and 15 are D-group acrocentrics; 21 and 22 are G-group
acrocentrics). This fusion, sometimes described as a
whole-arm exchange, is also called a Robertsonian translocation in recognition of the American cytogeneticist
Robertsons contribution from his studies of chromosome fusion in insect cytogenetics early in the twentieth century. Usually, the Robertsonian chromosome is
dicentric, although it may appear monocentric because
of suppression of one centromere.
Nonhomologous (sometimes called heterologous)
Robertsonian translocations comprise fusion of two different acrocentrics and are more frequent than homologous Robertsonian translocations. The prevalence of
the balanced rob(14q21q) translocation is about 1 in
10,000, and the rob(21q21q) is about one-third as frequent. About a third of translocation DS cases are inherited from one parent, and usually it is the mother who
is the balanced carrier. De novo rob(14q21q) DS also
originates most often in maternal germ cells (27) and is
due to a meiosis II nondisjunction event with an unusual
pattern of genetic recombination in meiosis I preceding
nondisjunction in meiosis II (28). Homologous Robertsonian translocations such as rob(21q21q) are mostly
isochromosomes but can be true translocations if they
are formed by fusion of maternal and paternal homologs
postconception (29). Only about 7% of DS individuals
with rob(21q21q) or rob (22q21q) have a carrier parent,
and the mother is usually the carrier.

43.3.2 Trisomy 21 Mosaicism

In 1% of cases, T21 mosaicism is present (30). The first
case reported in 1961 by Clarke and colleagues (31) was
a 2-year-old girl who was selected for detailed cytogenetic study because she had physical features of DS but
superior intellectual development. This girl had T21 in
13% of cells from blood leukocyte cultures and 34% of
cells derived from fibroblast cultures; the remaining cells
were 46,XX. There is a general tendency for the proportion of trisomic cells to be higher in fibroblasts and
in early life, so the proportion of trisomic cells in one
individual is not necessarily constant over time (32). In

CHAPTER 43 Autosomal Trisomies

general, in mosaic T21 the clinical signs of DS are less
prominent (32,33). Patients with low-level mosaicism
will likely be increasingly recognized with the utilization
of microarray (34). A low level of mosaicism in an unaffected individual may not have immediate clinical significance, but the mosaic trisomy parent may be at high risk
of offspring with full trisomy (35).

43.3.3 Prenatal Diagnosis

The incidence of DS increases in a nonlinear fashion and
ranges from approximately 1/1500 in women from 15
to 25years to 1/10 for a 48-year-old woman. The incidence remains constant between 15 and 25 and then rises
slowly between 25 and 35, increasing by a factor of 4
from 35 to 40 and by a factor of 10 between 40 and
45. Initially all screening efforts in DS were directed at
women at age 35 and older. This age was picked by consensus as the risk at that time was thought to approximately equal the procedure-related risks and to be cost
effective (36,37).
In practice, the actual procedure- related risks are
lower than originally thought. Some families place a high
value on the definitive knowledge from a diagnostic test,
even if there is risk, as they want the option of ending an
affected pregnancy. Other families, especially those who
have had prior unsuccessful or high-risk pregnancies, will
choose serum screening tests and ultrasound to avoid the
potential use of an invasive test (38). Based on these considerations, in 2007, the American College of Obstetrics
and Gynecology recommended that all women be offered
serum screening prior to 20weeks gestation and that all
women should have the option of definitive diagnostic
testing regardless of maternal age (39).

43.3.4 First and Second Trimester

Screening
Serum screening in the first trimester (1113weeks gestation) looks at two serum analytes, pregnancy-associated
plasma protein A (PAPP-A) and human chorionic gonadotropin (hCG). The abnormal values in DS are observed

(a)

(b)

empirically and are incompletely understood. Altered

placental function is an attractive hypothesis (40). Beta
hCG performs best between 9 and 13weeks of pregancy
and performance increases with increasing gestational
age (41). In contrast to hCG, PAPP-A performance
declines with increasing gestational age between 9 and
13weeks (42,43).
At the same time or shortly before or after first-
trimester serum screening there should be ultrasound
determination of the nuchal translucency (NT). A small
space in the posterior neck is a normal finding in all
first-trimester fetuses, but enlargement of this space is
associated with an increased risk of DS as well as other
abnormalities such as Turner syndrome, Noonan syndrome, or congenital heart disease (44). An enlarged
NT space is usually associated with distended jugular
lymphatics, which are commonly found in a number of
disorders. Even in an abnormal fetus the enlarged NT
often resolves later in pregnancy. Risks associated with
an increased NT should not be revised downwards even
if the measurements revert to normal later in pregnancy
(42). The optimal timing for the determination of NT
is 11weeks, but this can be performed between 10 and
14weeks gestation. Early studies of NT revealed significant intraoperator variability and variabilty based on the
quality of the ultrasound equipment. NT techniques have
been clearly delineated and involve measuring the nuchal
fluid space from inner to inner borders in a midsagittal
plane (Figure 43-1). Distinguishing the amnion, which
may not separate from the chorion until 16weeks, is
important, as the amnion can be confused with the posterior aspect of the fetal skin. Proper training and quality verification are now required elements in screening
programs utilizing NT (44,45). NT in combination with
serum screening can be used to determine those at very
high risk for DS and early invasive testing by chorionic
villus biopsy can be offered. In the State of California the
prenatal screening program has determined that NT measurements equal to or over 3.5mm constitute a risk for
aneuploidy of greater than 1/5 and that all such mothers
should be offered invasive diagnostic testing regardless
of serum screening results. Several studies have examined

(c)

(d)

FIGURE 43-1 Features of Down syndrome. (a) Brushfield spots. (b) Typical hand configuration with transverse crease and fifth finger
clinodactyly. (c) Sandal gapincreased space between toes one and two (d) Typical ear, which is small (<3%) with overfolded helix.

CHAPTER 43 Autosomal Trisomies

the risks associated with enlarged NT. In general, the

greater the enlargement the higher the risk for aneuploidy. Most fetuses with DS had NTs less than 4.5mm,
whereas fetuses with Turner syndrome and trisomies 18
and 13 had NTs in excess of 4.5mm (46). The distinction between an enlarged NT and cystic hygroma is not
entirely clear (47). In general, cystic hygromas tend to be
larger and extend along the length of the fetus and are
more often septated. Size, however, is the major determinant of outcome, probably not the distinction between
cystic hygroma and isolated increased NT (48).
The optimal detection of DS involves testing in both
the first and second trimester plus NT measurements.
As discussed earlier, screening in the first trimester consists of two analytes: PAPP-A and beta hCG, plus NT.
In the second trimester there are four analytes, which
include alpha fetoprotein (AFP), unconjugated estriol
(uE3), hCG and inhibin A, and these should be measured
between 15 and 20weeks gestation. When there is no
local availabilty of NT measurement, a serum integrated
test result can provide risk information, which has the
highest detection rate without an NT measurement.
The FaSTER (First and Second Trimester Evaluation
of Risk) trial looked at outcomes of pregnancy in 38,000
women followed in 15 centers in the United States who
underwent first- and second-trimester serum screening
plus or minus NT. At a detection rate of 85% there was
a 4.8% false-positive rate for first trimester plus NT; a
4.4% false-positive rate for serum integrated, a 0.8%
false-positive rate with fully integrated (plus NT) and a
7.3% false-positive rate for quadruple screening (43,49).
Many mothers do not enter prenatal care until the second trimester, and for such women the quadruple screening test (AFP, uE3, hCG and inhibin A) offers the best
screening strategy. Preferably such testing is done in conjunction with an ultrasound scan for fetal anatomy. This
can help refine risks, although ultrasound alone should
generally not be used as a primary screening tool.
The pattern of analytes differs in fetuses affected with
DS, T18, and SmithLemliOpitz syndrome. In DS, the
AFP and uE3 are depressed and hCG and inhibin are
increased. In T18, AFP, uE3 and hCG are all low, whereas
inhibin is unchanged. No risk information is obtained for
T13. Risk calculations include adjustment for maternal
weight, smoking, diabetes and multiple gestation.

43.3.5 Ultrasound Markers in

Trisomies 21, 18 and 13
The prenatal detection of aneuploidy is a major goal of
prenatal detection programs. Fetuses with T21 and T18
frequently have ultrasound evidence of congenital anomalies and, in addition, have what have been termed soft
markers, which increase the risk for aneuploidy, but are
also frequently seen in normal fetuses. These soft markers have no clinical sequelae by themselves and are usually fleeting, resolving by late gestation. The ultrasound

finding of an enlarged NT has been discussed. Other

markers seen more frequently in aneuploidy include echogenic bowel, absent nasal bone, pyelectasis, mild shortening of the long bones, echogenic intracardiac focus and
choroid plexus cysts. These findings can be seen in 11
17% of normal fetuses, but the presence of more than
one marker increases the risk for aneuploidy (50). There
has been significant controversy over the reporting of
echogenic foci and choroid plexus cysts, as they are most
often associated with a normal outcome and these findings provoke parental anxiety and may lead to invasive
testing. Review of the evidence suggests that the finding
of an isolated echogenic focus in the heart in an otherwise
low-risk woman does not increase the risk for aneuploidy
(5153). Choroid plexus cysts are present in 3050%
of fetuses with T18 compared to 13% of all secondtrimester fetuses; however, most large studies suggest
that an isolated choroid plexus cyst in the presence of
an otherwise normal fetal ultrasound is associated with a
normal karyotype (54,55). Combining multiple markers,
including serum screening, fetal NT and the presence or
absence of the nasal bone increases DS detection. In one
study, looking at these variables between 11 and 13 6/7
weeks in 20,000 pregnancies, 90% of DS was detected
with a 2.5% false-positive rate (56).
In the second trimester, ultrasound may help refine
the diagnosis of chromosomal aneuploidy. Over 1/3 of
fetuses with T21 have structural malformations, including
cardiac defects, central nervous system (CNS) anomalies
(especially ventriculomegaly), anomalies of the gastrointestinal tract (especially duodenal atresia), and facial findings including brachycephaly, small ears, cystic hygroma
and a thickened nuchal fold. A thickened nuchal fold is
the most sensitive (4050%) and specific (99%) single
marker for DS detection in the second trimester (57).
Soft markers such as mild long bone shortening, fifth
finger clinodactyly, and sandal gap great toe should not
be used as in isolation to detect DS in an otherwise lowrisk pregnancy. Studies have suggested that one should
not use second-trimester ultrasound alone to recommend
an amniocentesis in women who have had normal serum
screening. A study of 9000 women with abnormal serum
screening and a normal ultrasound revealed a reduced risk
of DS; however, in one study, about 45% of DS would
have been missed in the presence of abnormal biochemical screening and normal ultrasounds in women declining
amniocentesis. In addition, with normal serum screening results and an ultrasound with positive soft markers,
1200 amniocenteses would need to be performed to identify one fetus affected with T21 or T18 (58).
In T18, several second-trimester findings help identify
affected fetuses. These include overlapping fingers, clubfeet, components of the Dandy Walker malformation,
oral clefts, cardiac defects, micrognathia, omphalocele,
diaphragmatic hernia, renal abnormalities and single
umbilical artery. Intrauterine growth restriction and
polyhydramnios are also common ultrasound findings in

CHAPTER 43 Autosomal Trisomies

T18. The detection rate for T18 is higher than 90% by
combining ultrasound findings with abnormal first and/
or second-trimester serum screening. Conversly, if the
ultrasound is normal the risk of T18, even with abnormal serum screening, is low (59,60).
T13, the rarest of the autosomal trisomies, is associated with more severe structural abnormalities. Seventy five percent of T13 fetuses die in utero. Useful
ultrasound findings include holoprosencephaly, midline facial abnormalties, polycystic kidneys, cardiac
defects, neural tube defects, postaxial polydactyly,
ventriculomegaly and posterior fossa abnormalities.
Since some of these abnormalities can be visualized at
1114weeks gestation, first-trimester diagnostic rates
are high (61).
An exciting development in the prenatal diagnosis
of the major trisomies has been the analysis of cell-free
nucleic acids in maternal blood. The presence of fetal
material in the maternal circulation has been known
for some time. Initially in the 1990s, the isolation of
nucleated red blood cells along with fluorescence in situ
hybridization (FISH) and polymerase chain reaction
(PCR) allowed for detection of T21. The comparable
effectiveness of ultrasound and serum screening and their
lower costs kept this technology from acceptance in clinical practice, however. The knowledge that 36% of the
cell-free nucleic acids in maternal plasma are fetal in origin along with technical advances, including digital PCR
and massively parallel genomic sequencing, has led to
some optimism that first-trimester noninvasive screening
of maternal blood will soon allow for prenatal diagnosis
of the trisomies as well as single gene disorders (6264).
The postnatal confirmation of the diagnosis of T21
is critical to rule out a translocation or mosaicism and
usually involves routine karyotyping. Recent efforts to
reduce costs using new molecular techniques such as short
tandem repeats for chromosome 21 are promising (65).

43.3.6 Clinical Diagnosis

DS is characterized by a recognizable pattern of dysmorphic features, congenital malformations and other

(a)

(b)

health conditions. In newborns, eight cardinal signs

are redundant: neck skin, down turned mouth corners,
hypotonia, flat face, small typical ears, epicanthal folds,
sandal gap between first and second toes, and protruding tongue (66) (Figure 43-1). Clinical experience is an
excellent predictor of DS, but the occasional infant will
be atypical and cause even the most experienced clinician difficulty in diagnosis (25). Severe prematurity may
also lead to a late diagnosis, as the findings may be subtle in this group. Ethnicity affects ease of diagnosis: In
South Africa, delayed diagnosis was common in black
neonates in whom facial features of DS were less readily
recognized by the attending medical staff and by infants
mothers (67,68).
In children under 2years of age, 10 discriminating
clinical signs of DS are brachycephaly, oblique palpebral fissures, nystagmus, flat nasal bridge or root, narrow palate, folded ear, short broad neck, incurved fifth
finger, sandal gap between great toe and second toe, and
hypotonia (Figure 43-2) (69). The adult with T21 has
facial features that have changed with age (70) (Figure
43-2). The nasal root becomes more prominent, epicanthal folds become less prominent, and increased growth
of the lower face occurs, just as it does in chromosomally normal individuals (Figures 43-3 and 43-4). Older
literature photographs of adult individuals with T21
tend to reinforce old stereotypes, emphasizing features
such as obesity, abnormal tongue fissuring and an open
mouth.

43.3.7 Differential Diagnosis

In practice, one-third or more of requests for karyotyping to rule out DS give a normal result (25,71), but published clinical follow-up studies on the development of
the infants who test negative are lacking. More rarely,
features of the DS phenotype are present in cases with
cryptic chromosome 21q imbalance (72) or undetected
mosaicism for T21 (30). In newborns, Zellweger syndrome or tetrasomy 12p syndrome may be initially mistaken for T21. In older individuals, the facial appearance
of SmithMagenis syndrome can resemble DS. A new

(c)

FIGURE 43-2 The changing face of Down syndrome with age. (a) infant, (b) young child, and (c) 47-year-old adult (note hearing aid, gray
hair, edentulous).

CHAPTER 43 Autosomal Trisomies

FIGURE 43-3 Transient myeloproliferative disease in a hydropic

newborn with Down syndrome.

chromosomal syndrome that has a close facial resemblance is the microdeletion of chromosome 9q34 (73).

43.3.8 Development, Personality,

and Intellectual Disability
The stereotype of DS is a floppy, sociable, undemanding infant who turns into a placid, affectionate, goodnatured, music-loving, moderately intellectually disabled
adult. In fact, individuals with DS are just as different
from each other as their chromosomally normal peers:
some are happy and others are sad, some are flighty and
impulsive and others are careful and steady. Just as in
the general population, a minority of individuals exhibit
deviant behaviors or suffer serious conditions such as
autistic spectrum disorders (74). Overall, few individuals
with DS have serious behavioral disturbances (75,76).
There does appear to be a distinctive neurocognitive
phenotype (77).
Many changes in the brain and behavior in DS are
described (78,79), and correlation of structural CNS
findings with cognitive abnormalties has been studied
(80). Delayed myelination, reduction in growth of frontal lobes, narrowing of the superior temporal gyrus, and
reduction in size of the brainstem and cerebellum are
commonly reported neuropathologic changes in infancy.
In older children, there is reduced brain volume, especially affecting the hippocampus, and, from mid-adult
life onward, the predominant neuropathologies are
changes similar to Alzheimer disease (see later). In one
study, when followed over time there was a decrease in
IQ, correlating somewhat with the age-related findings
of early dementia and depression in DS adults (80).
Developmental delay becomes apparent during the
first year of life, with motor skills being the most obviously affected milestones. The average age of sitting is
11months; crawling 17months; walking 26months.
Children with DS develop speech in the same order as

typical children, but the rate is slow, with the average

time of first words at about 18months (8183). Parents
should be encouraged that almost all DS individuals will
learn to talk, although language is probably the most
impaired area of functioning, hampering attempts to
integrate individuals with DS into the community and
their efforts to live independently. Abbeduto and colleagues (84) present an extensive review of language
development in DS.
Virtually all children with DS have intellectual disability. Most are mildly to moderately impaired, with IQs in
the 5070 or 3550 range. Some are severely impaired,
with IQs of 2035. The most common pattern of impairment is for receptive language to equal the mental age of
the child, with expressive language being more delayed.
Vocabulary continues to increase and surpass mental age
in adolescence (85). Selective learning problems such as
difficulty understanding sequences or rules of grammar
have been described (86).
The histories of DS and Alzheimer dementia (AD)
have been linked for a very long time. The characteristic
brain findings of AD, including neuritic plaques, which
are extracellular deposits of amyloid beta protein in the
cerebral cortex and neurofibrillary tangles, are seen in
DS as early as age 8 and precede the development of
clinical dementia. It has previously been thought that
nearly all individuals with DS have characteristic brain
changes by 3540years, accompanied by clinical signs
of AD, particularily with frontal lobe involvement. More
recently, studies have suggested that the risks are slightly
lower, with 5070% of DS individuals having AD by
age 6070 (87). Along with the AD phenotype there is
evidence of generalized accelerated aging, documented
by age-related skin changes, osteoporosis, osteoarthritis,
hypogonadism and cataracts (88).

43.3.9 Growth
At birth, infants with DS show mild growth retardation,
with mean birth weight, length, and head circumference
lying between the 10th and 15th percentiles calculated
for chromosomally normal infants (89). In a study of
105 children with DS, length, weight and head circumference were below those of typical children and remained
lower until puberty, with the growth spurt occurring earlier than in the normal population (11 in boys and 9.5
in girls) (90). Growth charts for children with DS are
available in the United States and in several other countries (9194). Successful efforts have also been reported
to produce specific growth data for use in an electronic
medical record (95).
Obesity is common in DS (96), and it is suggested that
all those over 5years with weight over 75th percentile
should have the body mass index (BMI) charted. BMI
above 98th percentile is an indication for further assessment. The majority of children with DS are obese by
age three to four (82). The prevalence of obesity in DS

CHAPTER 43 Autosomal Trisomies

(BMI > 27.8/kg/m2 in males and >27.3/kg/m2 in adult
females) is greater than in the general population (45
and 56%). Obese women with DS may have better verbal memory, with a suggestion that higher endogenous
estrogen levels are contributory (97). Obesity in DS is
not due simply to increased food intake with deceased
energy expenditure. A systematic review of published
literature failed to provide convincing evidence that
increased aerobic exercise will improve physical or psychosocial outcomes (98). Intuitively, however, scheduled
training sessions in the company of peers encourage
friendship and social opportunities. Exercise also helps
to combat low bone mass and osteoporosis, which are
more prevalent in adults with DS (99,100).
Short stature is common in DS, especially in infancy
and adolescence. Stature is most reduced in children
with severe congenital heart disease (101). In addition,
several medical conditions causing poor growth, such
as celiac disease, are more common in DS. Medical and
dietary assessments are indicated when growth measurements lie below the second percentile (102). The cause of
most short stature in DS remains unclear. Low levels of
IGF1 and decreased levels of growth hormone have been
reported in some DS children (103).
Children with DS who are not growth hormone deficient do show a height response to growth hormone therapy (104,105), but such treatment is largely undertaken
on a research basis and is still being assessed in the longer term. Blanket prescription of growth hormone is not
recommended in the absence of proven growth hormone
deficiency (105). Results from a study in Sweden did not
demonstrate behavioral and cognitive improvements in
treated young children (104). A study in 2010 (106) on
early growh hormone treated children with DS revealed
a greater head circumference in DS as well as improved
performance on the Leiter and WISC III as compared to
control DS children. Further studies are needed.

43.3.10 Congenital Heart Disease

Congenital heart defects (CHDs) are present in approximately 44% of individuals with DS and all newborn
infants should undergo echocardiographic examination in the neonatal period. In the Atlanta Down Syndrome project, the breakdown of defects in the children
with DS was as follows. Atrioventricular canal defect,
comprising atrial septal defect with abnormality of the
atrioventricular valves and ventricular septum, with
or without other lesions, was seen in 45% of all CHD
cases (107). In fetal life about 50% of fetuses with isolated canal defects have T21. Isolated ventricular septal
defect with or without other lesions was seen in 35%,
isolated secundum atrial septal defect in 8% and patent ductus arteriosus in 7%. Tetralogy of Fallot and
other complex lesions made up the remaining 5%. In
two studies of adults with DS, mitral valve prolapse was
found in 46%, mitral regurgitation in 17% and aortic

regurgitation in about 7% of patients (108,109). This

has implications, as such individuals should probably
have prophylaxis for dental work to reduce the risk of
bacterial endocarditis (110,111).
Medical and surgical treatments of heart defects in
children with DS are similar to the treatments used in
the care of chromosomally normal children, with modern postoperative morbidity and mortality rates similar
in both groups (112,113); however, pulmonary hypertension is more common in DS (114,115). Postulated
precipitating factors include anatomic variations such
as maxillary hypoplasia and macroglossia, hypertrophy of the tonsils and adenoids, and sleep apnea with
or without upper airway obstruction. Coronary artery
disease, typically said to be rare in DS, may become
more frequent as the population of older DS individuals
increases (116).

43.3.11 Oral Health

Dental problems are common in DS. Malocclusion,
tooth grinding, and tongue thrusting can impair chewing, while periodontal disease, akin to juvenile periodontitis, is especially common and may reflect an underlying
immunologic predisposition. The tendency to poor oral
health in DS children can be improved by regular dental
care, at least as indicated by some studies (110,111,117)
Despite the prevalence of the periodontal problems,
caries may actually be less prevalent in DS individuals.

43.3.12 Gastrointestinal Complications

Gastrointestinal tract anomalies occur in about 5% of
children with DS (118). Two major gastrointestinal
anomalies associated with DS are duodenal atresia and
Hirschsprung disease. About 2.5% of infants with DS
have duodenal atresia or stenosis, sometimes in association with annular pancreas (86). About 2030% of
children with duodenal atresia have T21. Slightly less
than 1% of patients with DS have Hirschsprung disease,
which is higher than that in the general population (119).
Two percent of patients with Hirschsprung disease have
T21. A small number of T21 infants have both duodenal
atresia and Hirschsprung disease, and in such cases dual
pathology causes diagnostic problems because the presenting features of duodenal atresia overshadow signs of
Hirschsprung disease. For these two major gastrointestinal anomalies, surgical outcome in the short term can be
just as good as with chromosomally normal children, but
presence of additional cardiovascular and respiratory
malformations may lead to increase in delayed mortality
(120122).
Other congenital intestinal abnormalities that occur
more frequently in T21 infants include tracheoesophageal (TE) fistula, imperforate anus, omphalocele, duodenal bands, annular pancreas, ileal and jejunal atresias,
and microcolon (123). Esophageal motor disorders,

CHAPTER 43 Autosomal Trisomies

especially achalasia, are underdiagnosed complications

of DS (124,125).
Even in the absence of Hirschprung disease, constipation is a common complaint in children with DS, and
contributing factors are certainly hypotonia and relative
inactivity. In the adult with DS chronic unexplained diarrhea may be seen in up to 20% of individuals. In addition, Helicobacter pylori infection has been found in as
many as 66% of DS individuals (126).
Celiac disease has a biopsy-proven prevalence of
between 5 and 16% in DS individuals. In order to avoid
harmful consequences of undiagnosed and untreated
celiac disease, serologic screening of children and
adults using antiendomysial antibodies or tissue transglutaminase has been recommended, with biopsies for
screen-positive cases (127,128). Positive cases should
undergo small bowel biopsy. Negative cases should be
rescreened at intervals or have human leukocyte antigen
(HLA) typing that shows that they are not HLA DQ2 or
DQ8 (129).

Minor ocular findings in children and adults with DS

include epicanthal folds, up-slanting palpebral fissures,
and Brushfield spots on the iris (Figure 43-1). Asian children with DS seldom have Brushfield spots but do have
epiblepharon and exotropia (136). Brushfield spots are
also difficult to see in children with brown irides.
More important ocular complications, such as major
refractive errors, cataract, glaucoma, nystagmus (137),
nasolacrimal outflow drainage anomalies (138), and keratoconus (139), are important to detect. Therefore, all
individuals with DS should have frequent visual screenings, starting in the neonatal period. One protocol suggests first examination at 1month of age, then at 1year
of age, at 23years of age, at 56years of age (school
start), and every 5years thereafter (140). This should
detect the accommodation deficit that is present in a
majority of individuals and permit prescription of bifocal
or progressive lenses.

43.3.13 Otolaryngologic Problems

43.3.15 Hematologic Disorders

Ear, nose, and throat (ENT) complications cause much

morbidity in DS, and upper airway problems can be lifethreatening (130). Anatomic abnormalities affecting the
external and internal ear contribute to the high prevalence of middle ear infection and hearing impairment.
Hearing deficits occur in 3878% of individuals with
DS (131). The majority of DS children have a conductive hearing loss, 90% of which is caused by otitis media
with effusion. Stenotic ear canals, impacted wax, ossicular chain, and cochlear malformations are also common.
Ideally, all infants with DS should undergo newborn
hearing screening and be followed by clinical examination, pure tone or behavioral audiometry, and typanometry. It has been proposed that audiologic assessments
with maximum frequency between 6months and 1year
be performed, lessening in frequency thereafter and
continuing into adulthood (132).
For infants with hearing impairment, there is a trend
toward more aggressive treatment of conductive hearing
loss and early amplification (131), but early insertion of
polyethylene tubes and their regular replacement is not
without complication and does not guarantee improvement in expressive language.
One upper airway abnormality that merits special
mention is obstructive sleep apnea, a much underdiagnosed abnormality with multiple causes (133,134). Poor
growth, noisy breathing, apneahypopnea, disturbed
sleep, daytime sleepiness, and deterioration in behavior
can all be consequences of nocturnal oxygen desaturation and chronic hypoxia. Treatments are not always
successful but should be individually tailored in each
case, with consideration given to weight control, relief of
nasal allergies, and continuous positive airway pressure
during sleep (135).

Abnormalities affecting red cells, white cells and platelets are common in DS. At birth, 65% of DS infants have
polycythemia (141). Interestingly, the mouse model of
T21 demonstrates many of the same hematologic features of human DS including thrombocytosis, macrocytosis and a myeloproliferative disorder (142,143).
Neutropenia and macrocytosis are also common in DS
and the reasons are not known. Transient myeloproliferative disease (TMD) or transient leukemia almost
exclusively affects infants with DS. Recent work in
another mouse model for DS suggests that trisomy for
the gene ERG may underlie this phenotype, as reduction to disomy for ERG corrected the myeloproliferative
phenotype (144). The rate of TMD diagnosed prenatally
or postnatally is 20%.
A reported prenatal presentation of TMD is that
of generalized hydrops and is generally fatal (145)
(Figure 43-3). Most cases of TMD are asymptomatic
with resolution by 23months of age, but some have
severe disease (146,147). Presenting symptoms can
include hepatosplenomegaly, obstructive jaundice, liver
failure and ascites. Laboratory findings include leukocytosis; reduced, raised, or even normal platelet counts; and
low, high, or normal hemoglobin. TMD is characterized
by the presence of blasts in peripheral blood from a few
to >200,000L. With time the blasts decrease spontaneously. Unlike other forms of leukemia, the percentage of
blasts in bone marrow is lower than in peripheral blood.
Vesiculopapular skin findings are common, which may
be a clue to the presence of TMD, and these findings
resolve with hematological improvement (148,149).
Although spontaneous resolution in the first 3months
is usual, about 25% of affected children will, within
4years, develop myelodysplastic syndrome and acute

43.3.14 Opthalmologic Disorders

CHAPTER 43 Autosomal Trisomies

megakaryoblastic leukemia (AMKL) (150). Rarely, lifethreatening complications occur, including hepatic fibrosis and cardiopulmonary disease (151154). White cell
counts >100,000, direct hyperbilirubinemia, prematurity
and hydrops with ascites are associated with increased
risk of early death. Most patients do not require chemotherapy for TMD, but cases that do not resolve spontaneously or the high blast counts or liver dysfunction
occasionally improve with low-dose cytosine arabinoside. Usually there is rapid response, with clearing of
blast cells after about 7days of treatment (155). When
there is liver fibrosis the prognosis is poor, even with
chemotherapy. The overall mortality in TMD is about
20% (154).
T21 specifically predisposes to leukemia, with a risk of
11.5% (156). The type of leukemia that has the highest
relative risk of occurrence in T21 is AMKL. This leukemia arises in cells carrying somatic mutations in GATA1,
an X-linked gene encoding a hematopoietic transcription
factor seen invariably in AMKL, occurring prior to age
four. In contrast, acute myelogenous leukemia diagnosed
after age four is usually negative for GATA1 mutations.
The leukemic cells in AMKL that carry somatic mutations in GATA1 have been identified in transient leukemia blasts at birth, indicating that the somatic mutation
occurs in utero (157). In one study of GATA1 mutations,
three of four children with a GATA1 mutation detected
in newborn screening blood spots had AMKL diagnosed
at 1226months of age (158). Identification of GATA1
mutations at birth could serve as a marker for the development of TMD and later AMKL. In a 2011 study, 88%
of 134 DS patients with TMD had GATA1 mutations
and 85% of those DS patients with AMKL and DS had
GATA1 mutations (159). Thus, it is hypothesized that
the leukemia that arises in DS with somatic GATA1
mutations is a model for the stepwise process of leukemic
transformation.
Another theory proposed by Da Vita and colleagues
(160) is that disturbed early hematopoietic differentiation could be the cause of increased leukemia risk. They
postulate that if a common mechanism is behind the risk
of both major leukemia types, it would have to arise
before the bifurcation to myeloid and lymphoid lineages.
Using mouse embryonic stem cells bearing an extra
human chromosome 21 they analyzed the early stages
of hematopoietic commitment in vitro. They concluded
that overdose of more than one extra 21 gene contributes to the disturbance of early hematopoiesis in DS and
that one of the contributors is the gene RUNX1. As the
observed hyperproduction of multipotential immature
precursors in T21 precedes the bifurcation to lymphoid
and myeloid lineages, they speculate that this could create conditions increasing the chance for acquisition of
preleukemogenic rearrangements/mutations in both lymphoid and myeloid lineages during fetal hematopoiesis,
thus contributing to the increased risk of both leukemia
types in DS.

The risk of developing acute lymphoblastic leukemia (ALL) in DS is 1020 times higher than in control
children, accounting for 13% of children with ALL
(161). Clinical symptomatology is similar to that seen
in patients without DS. Mediastinal mass and CNS
leukemia, unfavorable signs, are less likely to occur in
patients with DS, as are T-cell leukemia and translocations 9;22 and 4;11. DS children, usually less than
10years of age, respond to chemotherapy as well
as control children with ALL. Children with DS are
more likely to experience severe toxicity with standard
chemotherapy regimens, particularly those requiring
methotrexate, and often require reduced doses of chemotherapy (162,163).
Children with DS and ALL have an increased number of deaths caused by infection, a decreased five-year
survival and more treatment-related complications as
compared to children with ALL who do not have DS
(150). These findings emphasize the need for providing
aggressive supportive care for patients with DS and ALL.

43.3.16 Immune System Abnormalties

Abnormalities in virtually all components of the immune
response have been reported in persons with DS. Commonly, immune system disturbances in DS manifest as a
predisposition to infection, malignancies and autoimmune
disorders, including celiac disease, diabetes mellitus, and
autoimmune thyroiditis. Infections in DS are likely to be
more severe and last longer than in typical children, and
despite advances in treatment of infections, hospitalization due to infection is significantly more common in DS
children. Immune factors are thought to play a role, but
certainly the presence of tiny ear canals, gastroesophageal
reflux and a small midface also contribute to infection risk.
The abnormalities of the immune system associated
with DS include mild to moderate T- and B-cell lymphopenia, with marked decrease in naive lymphocytes,
impaired mitogen-induced T-cell proliferation, reduced
specific antibody responses to immunizations and defects
of neutrophil chemotaxis. Limited evidence of genetic
abnormalities secondary to trisomy of chromosome 21
affecting the immune system is available, such as the
potential consequences of gene overexpression, most
significantly superoxide dismutase (SOD1). Decreased
intracellular killing in neutrophils is the most likely
manifestation of a dosage effect from increased SOD1
(164,165).
In a 2010 study, B-lymphocyte subpopulations in 95
children with DS were compared with 33 age-matched
control children. DS serum immunoglobulin levels were
compared with those of 962 non-DS children with recurrent infections. Transitional and naive B lymphocytes
were profoundly decreased in the children with DS. This
could be caused by an intrinsic B-lymphocyte defect
resulting in (partial) failure of B-lymphocyte generation,
decreased antigen-induced proliferation and/or increased

10

CHAPTER 43 Autosomal Trisomies

apoptosis, decreased proliferation due to deficient

T-lymphocyte help, or a combination of these. The
decreased number of CD27, CD21, and CD23 cells was
reminiscent of common variable immunodeficiency and
suggestive of disturbed peripheral B-lymphocyte maturation. Immunoglobulin levels in DS are subtly abnormal and different from those in non-DS children with
recurrent infections. These authors concluded that the
humoral immune system is abnormal in DS, but they
could neither find a relation between B-lymphocyte
subsets, immunoglobulins and clinical features of the
children with DS nor answer the question whether DS
lymphocytes are truly intrinsically deficient or are all
findings explained by deficient T-lymphocyte helper cells
(166). A 2011 study confirms the subtle abnormalities
in the immune system and reports a normal antibody
response to influenza vaccine but an impaired response
to pneumococcal vaccine (167).
Immunologic alterations are often age related and may
be one feature of a general, early-onset senescence in DS
(168). The thymus in DS has histologic abnormalities that
include reduced cortical area, thymocyte depletion, loss
of corticomedullary demarcation, enlarged cystic Hassall
corpuscles, and evidence of defective expansion of T-cell
precursors. Reduced expansion of T-cell precursors may
lead to an incomplete cell repertoire and abnormality of
cell-mediated immune response. Evidence suggests that
reduced thymic output and not peripheral output or
T-cell dysfunction contributes the immunologic features
of DS (169).
Most DS individuals do not have critical immunodeficiencies, but further study is needed to understand the
immunologic role in their repeated infections. Immunologic evaluation should probably be reserved for those DS
children with unusual and/or repeated infection, autoimmune disease, or other evidence of immunodeficiency.
Children with DS should receive the full childhood
immunization schedule, including yearly influenza
immunizations and pneumococcal vaccine. It is especially important for these children to receive hepatitis B
immunization, as there is a significant risk for chronic
carrier status (126).

43.3.17 Endocrine Disorders

Newborn infants with DS have levels of thyroid-
stimulating hormone (TSH) and thyroxine slightly
shifted to the right and left, respectively, compared with
the general newborn population (170). A recommendation that all DS neonates should be treated for mild
congenital hypothyroidism on the basis of evidence that
mental and motor development is improved in thyroxinesupplemented infants (171) requires further assessment.
Treatment is definitely required for severe congenital
hypothyroidism due to thyroid gland dysgenesis. There
has been the general conviction that hypothyroidism is
frequent in DS, with a frequency varying between 3 and

54% in DS adults (172). In view of the high frequency

of hypothyroidism and the nonspecificity of symptoms
and clinical signs such as lethargy, increased weight, constipation, depression, and dementia, regular surveillance
seems indicated. Health care guidelines published by
the American Academy of Pediatrics (15) suggest regular checks of thyroid antibodies and thyroxine and TSH
measurements at 12year intervals. A 15-year follow-up
study of hypothyroidism in 200 DS adults suggests that
clinical hypothyroidism is relatively uncommon and that
screening guidelines could be revised to suggest testing
only every 5years (173).
The risk of type 1 diabetes appears to be increased
in DS (174). Interestingly, in one study, age of onset of
diabetes was significantly earlier than in controls but diabetic control was better than in controls and less insulin
was required. Accompanying additional autoimmune
disorders were more frequent than in controls with type
1 diabetes (175). Diabetes was more likely to occur in
females and in those with obesity (176).
Fertility in DS differs by sex, with males being
generally infertile. This is probably due to impaired
spermatogenesis. A 2002 study of young adult males
with DS revealed normal levels of FSH, testosterone
and dehydroepiandosterone but showed elevated levels of luteinizing hormone (LH) and 17-OH progesterone (100). Rarely there have been reports of fertility in
males. Females with DS appear to have normal menarche (12.6years). There may be subtle abnormalities
of the pituitaryadrenal axis, with increased levels of
prolactin, LH, testosterone and 17-OH progesterone
(100). DS women appear to have reduced fertility, but
this may be due to lack of opportunity. Pregnancy has
been reported on multiple occasions. Appropriate counseling and contraception are indicated for DS women.
A higher rate of early menopause has been reported in
women with DS (177).

43.3.18 Craniovertebral Junction

Abnormalities, Including Atlantoaxial
Subluxation
Atlantoaxial subluxation is a serious but infrequent complication of DS that causes neurologic symptoms and
signs of spinal cord compression, including sudden or
gradual onset of neck pain or postauricular pain, head
tilt, ataxia, limb weakness, loss of bowel or bladder control, increased tendon reflexes, and spasticity. Such signs
may occur at any age and are an indication for immediate referral to a specialist for investigation and, in some
cases, surgical treatment (178).
In contrast, atlantoaxial instability is defined radiologically as an atlantoaxial gap of greater than 4mm
that may be observed, without any symptoms or clinical
signs, in lateral-view radiographs of the cervical region in
full flexion and extension. Instability probably does not
predict increased risk of cord compression and seems to

CHAPTER 43 Autosomal Trisomies

have little or no predictive value for subsequent acute dislocation or subluxation at the atlantoaxial joint, such as
might occur with a sports trauma or neck manipulation
in the course of unguarded anesthesia (179,180). The
American Academy of Pediatrics committee on genetics
advises that a single radiograph should be obtained and
such a radiograph may be required by organizations such
as the Special Olympics prior to the childs or adults
active participation (15).
In older DS adults, the degree of ligamentous laxity
lessens but degenerative cervical spine abnormalities may
occur.

43.3.19 Neurologic Problems

Epileptic seizures are more common in DS individuals
than in the general population. The prevalence of seizures
peaks in infancy and in late adult life. Diagnosis remains
clinical and is crucially dependent on a reliable history
and accurate observation (181). The electroencephalogram may clarify the type of epilepsy and help manage
treatments of certain epilepsies. Infantile spasms, myoclonic epilepsy, clonic seizures, reflex atonic seizures, and
febrile seizures have all been reported.
In adults, onset of epileptic seizures, especially myoclonic epilepsy, is associated with the onset and progression of dementia (182,183). Other signs of dementia are
personality change, cognitive decline, gait deterioration,
loss of daily living skills, and incontinence. Functional
decline in adults with DS is also a feature of treatable
conditions such as depression and hypothyroidism.
The prevalence of dementia in DS rises from 10% at
50years to more than 75% at over 60years of age. Males
with DS are more likely to become demented. Genotyping within 43 single-nucleotide polymorphism (SNPs)
within 28 genes revealed significant associations with
APOE, SORL1, RUNX1, BACE1 and ALDH18A1,
with the strongest associations with APOE (184).
Alzheimers in DS is characterized by a specific type of
slow and progressive neurodegeneration, which involves
the abnormal hyperphosphorylation of the microtubule
associated protein (MAP) tau. This hallmark, called neurofibrillary degeneration, is seen as neurofibrillary tangles,
neuropil threads, and dystrophic neuritis. Apparently
required for the clinical expression of AD, and related
tauopathies, it leads to dementia in the absence of amyloid plaques. While normal tau promotes assembly and
stabilizes microtubules, the nonfibrillized, abnormally
hyperphosphorylated tau sequesters normal tau, MAP1
and MAP2 and disrupts microtubules. The abnormal
hyperphosphorylation of tau, which can be generated
by the catalysis of several different combinations of
protein kinases, also promotes its misfolding, decrease
in turnover, and self-assembly into tangles of paired
helical and or straight filaments. Some of the abnormally hyperphosphorylated tau ends up both amino and
C-terminally truncated. Disruption of microtubules by

11

the nonfibrillized abnormally hyperphosphorylated tau,

as well as its aggregation as neurofibrillary tangles, probably impair axoplasmic flow and leads to slow progressive retrograde degeneration and loss of connectivity of
the affected neurons (185).
Neuropathologic studies of adults with DS reveal
cerebral amyloid (amyloid) plaques and neurofibrillary tangles. In young DS patients, there is evidence of
intraneuronal amyloid in the hippocampus and cerebral
cortex, and it is proposed that intracellular deposition
precedes extracellular amyloid, followed by diffuse and
neuritic plaques in the third decade and neurofibrillary
tangles after age 40years (186,187).
Patients with Alzheimer dementia have reduced cerebral production of choline acetyl transferase, which leads
to a decrease in acetylcholine synthesis and impaired cortical cholinergic function. Adults with T21 might benefit
from acetylcholinesterase inhibitors, which in clinical
trials have conferred benefits to mildly and moderately
affected Alzheimer disease patients. Results from treating small-sample-size populations of DS individuals
have been favorable, but larger randomized studies are
required (188).

43.3.20 Trisomy 21: Factors Influencing

Chromosome Nondisjunction
Hassold and Sherman (189) reviewed their own studies
and those of others who examined chromosome 21 DNA
polymorphisms to demonstrate that approximately 90%
of T21 cases result from a maternal meiosis nondisjunction error, 75% of which occur at maternal meiosis I. In
cases in which the extra chromosome is paternal in origin, meiosis I and meiosis II nondisjunctions are equally
frequent. The low frequency of a paternal origin may be
due to a very low percentage of testicular mosaicism as
compared to that seen in the ovary (190). Mosaic T21
may have postzygotic origin or be caused by a maternal
meiotic error leading to trisomy in the zygote followed
by loss of the extra chromosome during a mitotic cell
division (191).
Chromosome recombination in oocytes occurs
before birth, and the pattern of chromosome 21 genetic
recombination affects susceptibility to nondisjunction
(192,193,194). In one study, younger mothers of T21
cases had more pericentromeric and telomeric exchanges
that increase susceptibility to nondisjunction, whereas
older mothers of T21 cases had exchange patterns that
mimicked the patterns observed in normally disjoining
chromosome 21s. This, it was argued, suggested that the
greatest risk factor for nondisjunction in younger women
is a susceptible exchange pattern (195). The two-hit
model suggests that ovaries of older women may be less
efficient at rescuing the susceptible-to-nondisjunction meiosis I exchange pattern because of age-related
perturbations in meiotic machinery (194). The spindle
checkpoint delays the cell cycle when meiotic or mitotic

12

CHAPTER 43 Autosomal Trisomies

chromosomes are not properly attached to the spindle; spindle checkpoint proteins are being investigated
to determine if gradual decline in the efficiency of the
checkpoint explains maternal age-related probability of
aneuploidy (196,197).
As maternal age-adjusted DS rates vary little across
human populations (198), these are unlikely to be greatly
influenced by environmental factors such as periconceptional multivitamin use (199), but putative associations such as between poor socioeconomic status and
maternal meiosis II error, and between parity and DS,
have been examined (200,201). Other factors put forward that might influence nondisjunction rates include
changes in follicular development unrelated to the size of
the oocyte pool (202,203); reduced ovarian complement,
whether due to congenital absence or surgical removal
(204); and accumulation of spontaneous mitochondrial
DNA deletion mutations that diminish the supply of
energy to cells surrounding the oocyte (205). Inheritance
of methylenetetrahydrofolate reductase (MTHFR) gene
polymorphisms has been linked to chromosome 21 nondisjunction. Examination of transmission frequencies
of the MTHFR 677T and 677C alleles from heterozygous parents to children with DS revealed that the 677T
allele was transmitted to children with DS at a significantly higher rate and the 677C allele was transmitted
at a significantly lower rate (206). Most conceptions
with T21 end in pregnancy loss, and it was proposed
that preferential transmission of the 677T allele in this
population of live-born infants with DS could reflect a
survival advantage. A putative association between birth
of a child with folate-associated neural tube defect or
hydrocephalus and increased risk of T21 is controversial (207,208). A 2010 study looking at predispositon
to congenital heart disease in DS studied a group of 121
case families (mother, father, and proband with DS and
CHD) and 122 control families (mother, father, and proband with DS and no CHD); tag SNPs were genotyped
in and around five folate pathway genes: 5,10-MTHFR,
methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine beta-synthase (CBS), and
the reduced folate carrier (SLC19A1, RFC1). SLC19A1
was found to be associated with CHD using a multilocus allele-sharing test. In addition, the known functional
polymorphism MTHFR C1298A was overtransmitted to
cases with CHD and undertransmitted to controls. The
authors concluded that the disruption of the folate pathway contributes to the incidence of CHD among individuals with DS (209). In summary, altered patterns of
genetic recombination appear to be a common risk factor for T21 and for other maternal meiosis I trisomies,
but the size and direction of the alteration varies with
the chromosome involved (210). In addition, alterations
in the folate pathway genes may impact the occurrence
of congenital heart disease and possibly other defects
in DS. A chromosome-nonspecific tendency to nondisjunction may explain why there is a slight excess of

other autosomal aneuploidies in women who have had

a DS pregnancy at a young age (see Down Syndrome
Recurrence Risks later) (211,212).

43.3.21 Chromosome 21 Down Syndrome

Critical Region
Identification of cases with clinical features of DS in association with duplication of specific regions of chromosome 21 (Figure 43-5) led to the designation of a Down
syndrome critical region at 21q22qter, hypothesized to
harbor the most influential genes, extra copies of which
determined most if not all DS features (213). At the same
time, the developmental instability hypothesis proposed that DS features arose from specific disruptions of
genetic homeostasis rather than from direct gene dosage
effects (214). Fitzpatrick (215) incorporated both ideas
in a testable hypothesis, proposing primary gene dosage
abnormalities with sequential and complex transacting
effects on disomic genes. Experimental evidence followed publication of the chromosome 21 DNA sequence
with detailed annotation revealing over 200 genes, which
is only half the number of genes on chromosome 22
(216,217).
Mouse models of DS have been generated because of
the synteny existing between human genes on chromosome 21 and mouse genes on chromosome 16 (26.5Mb),
chromosome 10 (2.3Mb) and chromosome 17 (1.1Mb).
Two kinds of murine models have been developed to investigate the molecular genetics of DS: segmental trisomic
and transgenic models (218). The trisomic mouse mimics much of the clinical phenotype of DS, but single gene
effects are difficult to analyze. In the transgenic mouse
the effects of one or few genes can be studied in detail.
Detailed statistical analysis of cranial shape in different
trisomic mouse models (Ts1Cje, Ts65Dn, and Ms1Rhr/
Ts65Dn) have shown that DS critical region genes alone
are neither sufficient nor (largely) necessary to produce
characteristic mouse craniofacial dysmorphology (219).
This important study proposed that, in DS, triplicated
genes have inconspicuous solitary effects but do contribute to the overall phenotype in combination with
other genes, through as yet unidentified specific effects
and interactions. Gene expression studies in Ts65Dn
mice also point to complex regulation of expression of
the aneuploid genes, since only a third are expressed at
the theoretical 1.5-fold level, with significant proportions being expressed at levels above and below 1.5-fold
(220). In yet another mouse model, there is evidence that
triplication of the genes in the DS critical region does
confer a characteristic neurological and behavioral phenotype (221). In several transgenic mouse models the
important genes in the critical region, DYRK1A and
RCAN1, have been shown to contribute to the learning
and memory deficit, altered synaptic plasticity, impaired
cell cycle regulation, and AD-like neuropathology in
DS (222). Increasing evidence suggests that there is not

CHAPTER 43 Autosomal Trisomies

a single DS critical region but a number of susceptibility regions on chromosome 21, which are modified by
other genes on chromosome 21 and genes elsewhere in
the individuals genome. A review by Ruparelia and colleages (223) summarizes how overexpression of genes on
chromosome 21 contributes to the pathogenesis of DS.
Whether or not the mouse phenotypes are directly applicable to high-level behavior and learning necessary for
normal human development remains unclear. Nevertheless, better understanding of the complex genetic origins
of the abnormal behaviors in the mouse model as well as
illustrative human case reports, aid human DS genotype
phenotype analysis (224,225).

43.3.22 Down Syndrome Recurrence Risks

43.3.22.1 Trisomy 21 and Mosaic Trisomy 21
Recurrence Risks. Hook (226) summarized data on
the chance of recurrence of T21 in children of mothers
who had one live-born affected infant: when the mother
was of age under 30, the recurrence risk was 1.4%, and
this figure was clearly increased above the background
rate of about 0.7%. But when the mother was older,
the T21 recurrence risk was not clearly increased above
the background maternal age risk. Hook also reviewed
evidence from amniocentesis data that older women
who had their first affected pregnancy under age 30 were
more likely to have greater underlying predisposition to
recurrence compared with older mothers who had their
first affected pregnancy after age 35years.
Hooks conclusions were confirmed in three more
recent studies. Employing North American, United Kingdom and Australian data, Warburton and colleagues
(227), De Souza and colleagues (212) and Morris and
coworkers (5) compared observed numbers of trisomies at
prenatal diagnosis with expected numbers. Comparisons
of recurrence rates after diagnosis of the same trisomy
(homotrisomy) and of a different trisomy (heterotrisomy)
showed that younger women had the highest recurrence
risk for homotrisomy, with both the index T21 and subsequent prenatal diagnosis at age less than 30years. The
risk was less for women with both pregnancies at age
greater than or equal to 30years. The study from the
United Kingdom (4) showed women who had had a previous DS pregnancy have a constant absolute excess risk
above their maternal age-related risk of having a subsequent affected pregnancy. The excess was determined by
the age at which the affected pregnancy occurred and was
considerably higher for women less than 30years and
negligible in women greater than 40years.
When counseling families, these various recurrence
risks may be perplexing. One approach is to emphasize
that the overall chance of recurrence of T21 is still low:
at about 1% at the time of prenatal diagnosis for mothers less than 30years of age, this figure represents a sixto eightfold increase in the age-related risk; for mothers
aged 3140years who had the index case in their 30s, the

13

age-related risk may be doubled; and for mothers over

40years, there is negligible change in the maternal agerelated risk. The chance of recurrence for any other viable trisomy after an index case with T21 may be double
the age-related risk.
43.3.22.2 Two Previous Trisomy 21 Conceptions.
About 3% of couples have a greater risk of recurrence
of DS because of the presence of somatic or gonadal
chromosome mosaicism in one parent (228). Such couples might have three or four pregnancies affected by
trisomy 21. De novo recurrence of the same trisomy is
another possibility, but studies suggest that the origin
of recurrence is much more likely to be due to low-level
oocyte mosaicism (228,229). Kovaleva (228) and Delhanty (229) evaluated records or literature reports on
80 families with recurrent T21. Postzygotic rescue of
T21 due to error in meiosis I was proposed as a mechanism of parental gonadal mosaicism formation in 78%
of the families with known origin of the T21. For the
other 22%, rescue of errors in meiosis II or postzygotic
mitotic nondisjunction was assumed. Mosaicism for T21
in successive generations has been reported in at least
12 families. Kovaleva and Delhanty (229) hypothesize
that in many cases the mother was a trisomic conception
with postzygotic trisomy rescue. It is interesting that in
proven maternal mosaicism the maternal grandmother
was over 35 at the time of the mothers conception.
Parental gonadal mosaicism (mostly maternal) may contribute significantly to the occurrence and recurrence of
DS in young women. In counseling of families with a
recurrence, a suggested 1020% represents an educated
guess for the risk of a third pregnancy with T21. Preimplantation genetic diagnosis may be an option for some
families with an apparently high recurrence risk (230).
43.3.22.3 Parent with Trisomy 21. Women with T21
may become pregnant, and in this situation the risk of
T21 in the offspring is close to 50%. Fertility in males
with T21 is exceptional, but there are at least three welldocumented reports of an affected male fathering an
unaffected child (231).
43.3.22.4 Translocation and Isochromosome 21
Down Syndrome. Following the diagnosis of translocation 21 or isochromosome 21 DS, if both parents have
normal blood chromosomes, the translocation or isochromosome is usually presumed to have arisen as a result of
a new mutation (de novo), and the observed recurrence
risk in a series of translocation cases was less than 1%
(232). Gonadal mosaicism for isochromosome 21 has
been reported and recurrences of DS are recorded (233),
so a rounded-up 1% risk of recurrence is appropriate,
and prenatal cytogenetic diagnosis should be offered to
cytogenetically normal parents who had a fetus or child
with DS due to a de novo structural abnormality.
Where one parent is shown to carry a balanced
Robertsonian translocation that has given rise to a child
affected by DS, the risk of recurrence mainly depends
on the sex of the carrier parent: if the mother is a

14

CHAPTER 43 Autosomal Trisomies

rob(14q21q) carrier, the risk of recurrence at amniocentesis is 15% (closer to 10% at term because of fetal
demise after 16weeks gestation), compared with a
much lower risk of less than 5%, even less than 1%, if
the father is the translocation carrier. In parental translocation carriers of both the 14/21 translocation and the
13/14 translocation recurrence risk data was confirmed
in a study of embryos from preimplantation genetic diagnosis (234). Although data are scanty, the same risks and
sex difference most probably apply to other heterologous
Robertsonian translocations involving chromosome 21
(rob (13q21q), rob(15q21q), and rob(21q22q).
Translocation interchange T21 is a rarer cytogenetic
variant that has been reported in more than 20 families
with reciprocal translocations involving chromosome
21q. Usually, a large chromosome (numbers 1 through
12) is involved, and there is underlying 3:1 segregation,
most often in the carrier mother, with a high risk of
recurrence (235).
43.3.22.5 Family History of Down Syndrome. When
the proband has confirmed T21, relatives other than the
probands parents may be advised that their positive
family history does not confer an appreciably increased
risk of T21, except, of course, when the family history
absolutely suggests otherwise. Gair and colleagues (236)
reported one such family with four cases of T21 in three
generations.
In the case of an affected individual with unknown
karyotype, based on the mothers age at the birth of the
proband, the probability of translocation DS is very low
when the mother is over 35years and no greater than
10% at the youngest maternal age. Therefore, chromosome analysis carried out on a parent with a positive
family history of DS rarely discloses a balanced Robertsonian translocation. Chromosome analysis may be
offered to an expectant relative with explicit understanding that a normal result does not abolish risk of
an abnormal pregnancy outcome. Aside from other
chromosomal or inherited syndromes being mistaken for
DS, cryptic or submicroscopic translocation involving
chromosome 21q may cause recurrent DS with a normal
karyotype (72).

43.4 TRISOMY 18
T18, or Edwards syndrome, was first diagnosed cytogenetically 1year after T21 (237). It is the second most
common trisomy. Neonatologists and pediatricians are
usually familiar with the characteristic presentation and
medical course of this serious trisomy.

43.4.1 Clinical Diagnosis

T18 is usually not a difficult clinical diagnosis, but may
present difficulties to less experienced clinicians and in
the setting of a neonatal resuscitation when the phenotype may be more challenging to appreciate. The

craniofacial features include dolichocephaly and a small

triangular face that is seen by parents as cute but to
the professional as distinct. The forehead is high, occupying more than one-third of the face. The nasal bridge is
high for age and palpebral fissures often slant down and
are short. The mouth is characteristically small, making
intubation difficult. There is accompanying micrognathia. The ears have been called windswept because of
posterior rotation and the helices are often poorly delineated. Preauricular tags and pits are not infrequent. The
sternum is subjectively and objectively short. The hands
reveal overlapping fingers, second and fifth over third and
fourth (Figure 43-4). Nail hypoplasia is a consistent finding and is very helpful diagnostically. Phalangeal flexion
creases are reduced to absent, especially distally. Prominence of the heels with convexity of the soles (rockerbottom feet) and short, dorsiflexed great toes with a slight
degree of second and third toe syndactyly are useful signs
(Figure 43-5). The genitalia are often underdeveloped,
with a characteristic decrease in fat stores of the mons
veneris area in females. The neurological exam can reveal
either hypotonia or hypertonia. General responsiveness is
decreased and apnea/bradycardia are frequent findings.
Structural birth defects are common, including congenital heart disease, esophageal atresia, omphalocele and the
Dandy Walker malformation and its variants.

43.4.2 Prenatal Diagnosis

The prenatal diagnosis of T18 is accomplished by a variety of means depending on when the mother presents
in pregnancy. There is increasing diagnosis in the first
trimester because of early serum screening, NT determination and characteristic sonographic findings. In one
study of 53 cases of T18 in the first trimester, all but one
fetus had one or more sonographic abnormalities, the
most common of which were an increased NT (91%),
hypoplastic nasal bone (53%), generalized subcutaneous edema (49%), omphalocele (21%) and early growth
restriction and bradycardia (26%) (238). This study confirms reports by Breathnech etal. (50) and Wapner etal.
(239). First-trimester serum screening showing decreased
levels of PAPP-A and decreased beta hCG are also helpful and may direct patients to early definitive testing via
chorionic villus biopsy.
In mothers presenting for the first time in the second
trimester there are a number of helpful diagnostic modalities. Serum quadruple screening provides useful information, which in combination with ultrasound can lead to
accurate detection via invasive testing or a high suspicion
of this diagnosis in women declining amniocentesis. The
most common second-trimester findings in T18 include
congenital heart disease, posterior fossa abnormalities in
the Dandy Walker spectrum, choroid plexus cysts, and
ventriculomegaly (240,241). Craniofacial abnormalities
are frequently diagnosed by ultrasound with some specificity as to the chromosome involved (242). An isolated

CHAPTER 43 Autosomal Trisomies

(a)

15

(b)

FIGURE 43-4 Two infants with trisomy 18. Note triangular face, small mouth, downslanting palbebral fissures, overlapping fingers, and short
sternum.

(a)

(b)

FIGURE 43-5 Trisomy 18. (a) Overlapping fingers in fetus. Note severe nail hypoplasia. (b) Rocker bottom foot.
choroid plexus cyst is a frequent normal developmental
finding, which resolves in the third trimester, and in the
absence of other findings is unlikely to be due to T18
(55). On the other hand, large and/or multiple choroid
plexus cysts in the presence of other consistent anomalies are strongly suggestive of T18. A study by Lai and
colleagues (243) reviewed 10years experience with 69
diagnoses of T18. The detection rate of fetal anomalies by ultrasound was 93% at <14weeks and 100% at
1821weeks. A normal detailed ultrasound with normal
fetal growth and normal amniotic fluid in the midtrimester essentially rules out T18.
A definitive diagnosis of T18 by chorionic villus biopsy
or amniocentesis should prompt careful counseling of
the family, which should take into account the familys
cultural and religious beliefs. Most families receiving this
diagnosis will elect termination after considering fully
this serious handicapping condition. Some families will
want to continue the pregnancy and should be supported
in this decision (244). There should be a dialog between
the obstetric/neonatal team and the family to achieve
decisions that will be in the best interests of the child.
The practice of prenatal consultation with the family and

the neonatal team should be encouraged so that a birth

and neonatal plan can be agreed upon prior to delivery.
Merritt and colleagues (245) present an excellent comprehensive review of these complicated issues. Avoidance
of cesarean section when fetal distress occurs in labor
should be proposed to the family. Optimally the family
will decide on vaginal delivery and supportive comfort
care for the infant. Some families insist on doing everything for the baby even when all the facts are presented.
This clearly presents a conflict between the physicans
understanding of the medical facts and families desire
for autonomous decision making for their infant. In general, obviating the infants pain and suffering and avoiding escalation of care, including intubation, should be
goals for both families and treating physicians. These
situations may present serious ethical challenges to the
health care team (245247). Ethical issues more commonly arise when there is no knowledge of a definitive
diagnosis prenatally because of late prenatal care, refusal
of diagnostic testing, or parental denial of the findings on
ultrasound. In these situations, urgent consultation after
birth by an experienced geneticist can lead to confirmation of the suspected clinical diagnosis and fact-based

16

CHAPTER 43 Autosomal Trisomies

supportive counseling. Utilization of a neonatal palliative care team, if available, and use of local infant hospice
resources should be encouraged and can help families
and health care providers achieve mutual goals for the
infant and family. Even with full intervention including
surgery and ventilator support the outlook for long-term
life seems not to be improved, and these are the facts that
families should understand in their decision-making.
A clinical diagnosis should always be confirmed by a
postnatal karyotype or FISH. Array comparative genomic
hybridization (array) will also confirm this diagnosis,
but is an expensive option when the clinical diagnosis is
unambiguous. FISH and array studies can be particularly
useful on formalin fixed tissue when the infant is stillborn and/or macerated and routine karyotyping is not
successful.

43.4.3 Natural History

Case reports, epidemiologic studies, and interviews with
parents have provided data on the natural history of T18
(7,248252). After cytogenetic confirmation or a firm
clinical diagnosis, parents may be told that median survival is 12weeks, 90% of babies die by 6months, and
only 510% are still alive at age 1year. Congenital heart
disease or cardiopulmonary arrest are frequently stated
to be the cause of death in T18, but this may be an oversimplification, with ill-defined CNS abnormalities and
respiratory system problems contributing to central
apnea (246).
Cardiac anomalies are common in surviving infants,
with cyanosis present in the majority of newborns. The
most common lesions are large septal defects and patent ductus arteriosus. Valvular dysplasias are present
in most cases but are not associated with significant
regurgitation or stenosis. Doppler evidence suggestive
of elevated pulmonary artery pressure (low-velocity
bidirectional flow across the ventricular septal defect
and patent ductus arteriosus) is accompanied by greater
than normal mean right ventricular cavity and free wall
dimensions. The combined findings of frequent cyanosis and increased right ventricular dimensions suggest
that factors such as pulmonary hypertension may contribute to early death. Cardiac surgery is not usually
performed in the United Kingdom and Europe, but is
more frequently undertaken in the United States and
Japan (253). A recent survey of clinicians carrying for
these infants suggested that care takers often do not
agree on their approach to recommending or offering
surgery to these infants, with cardiologists more likely
to offer intervention than neonatologists or geneticists
(254). The literature on infants who have undergone full
therapeutic interventions is not encouraging with respect
to improving long-term survival. One study examined
the outcomes of cardiac surgery in 34 patients with T18.
Survival over the short term was statistically slightly better in the group of nine undergoing surgery, but the rate

of being discharged home alive was no different in the

two groups (255).
In older survivors, profound physical and intellectual
disability is inevitable and overall development usually
does not progress beyond that of a 6-month-old, chromosomally normal infant. Vision and hearing impairments
may be severe (256). Somatic growth is poor (257), and
skeletal abnormalities such as severe kyphoscoliosis are
frequent (258). Infection causes morbidity and mortality (259). Various malignant tumors are infrequently
reported, including Wilms tumor (260) and hepatoblastoma (261).

43.4.4 Differential Diagnosis

PseudoT18 syndrome was formerly diagnosed in
infants with some signs of T18, such as prominent
occiput, abnormal ear helices, short palpebral fissures,
distal limb contractures, and profound developmental
retardation, who had a normal karyotype. PseudoT18
is practically never diagnosed today, but syndrome
delineation in such challenging infants remains difficult. A rare condition that may resemble T18 includes
Bowen-Conradi syndrome caused by mutations in the
ribosome biogenesis gene EMG1. Infants with this
autosomal recessive condition first described in the
Hutterites, have many of the same features seen in T18
and have an equally poor prognosis for life and mental development (262). The heterogeneous Marden
Walker syndrome may have similar hand findings along
with an immobile face and growth restriction. The
complex and heterogeneous syndromes termed Pena
Shokeir or cerebral ocular facial syndrome (COFS) are
encompassed by the term fetal akinesia deformation
sequence (FADS). This phenotype can be seen when a
mother has myasthenia gravis with high titers of antiacetylcholine receptors (263). In addition, FADS can be
caused by homozygous mutations in DOK7 or RAPSN
(264,265). Other autosomal recessive causes of FADS
await gene discovery. Autosomal recessive variegate
aneuploidy with multiple mosaicism including T18
cells has also been reported. Using exome sequencing, this was recently found to be due to homozygous
mutations in CEP57, a centrosomal protein involved
in nucleating and stabilizing microtubules. The study
indicates the crucial role of CEP57 in maintaining correct chromosome number in cell division(266). Distal
arthrogryposis may present in the newborn period
with a T18like hand, but lack of other features such
as growth restriction and major anomalies reflects its
much better prognosis.

43.4.5 Mosaic Trisomy 18

The phenotypes displayed by cases of T18 mosaicism
range from full T18 syndrome through a milder, nonspecific, dysmorphic phenotype often but not always

CHAPTER 43 Autosomal Trisomies

associated with growth deficiency (266) to a normal
phenotype in cases ascertained serendipitously. If blood
chromosomes are normal, clinical signs such as asymmetry of body proportions or cutaneous pigmentary abnormalities (267) are indications to undertake cytogenetic
analysis of skin fibroblast cultures. Conversely, full T18
in blood cells with an unexpectedly mild clinical course
should suggest chromosome mosaicism with a euploid
cell line in other tissues (268).

43.4.6 Cytogenetics of Trisomy 18

T18 syndrome is almost always due to three copies
of chromosome 18, and, like T21, T18 is a maternal
age-related autosomal trisomy with the rate at prenatal diagnosis or birth rising until 43years and then leveling off (269). Studies employing polymorphic DNA
markers indicated that the extra chromosome in T18
is usually of maternal origin; however, in contrast to
T21, wherein maternal meiosis I errors are most frequent, maternal meiosis II errors predominate in T18
(193). Chromosome-specific factors complicate the
simple model of susceptible chiasma distributions interacting with age-dependent deterioration of the meiotic
mechanism. For chromosome 18, 30% of tetrads are
nullichiasmate in maternal meiosis I nondisjunction,
but nullichiasmates are not observed in maternal meiosis II nondisjunction. Maternal meiosis I errors, paternal meiosis errors, and post-zygotic errors do occur in a
minority of T18 cases (270).
Very few cases are associated with translocations or
any other chromosome 18 structural abnormalities such
as the true 18q isochromosome (271). Detailed phenotypekaryotype correlations have thus been possible in
a few cases only and led to the conclusion that no single
region on 18q is sufficient to produce the T18 phenotype. Proximal and distal regions of 18q are both important, and severe mental retardation is associated with
18q isochromosome (272,273).

43.4.7 Trisomy 18 Recurrence Risk

Recurrence of T18 is exceptionally rare, but over 40years
ago Hecht and colleagues (274) suggested increased risk
of DS in families in which the index case had T18. Since
then, there have been many recorded instances of occurrence in a sibship of T18 followed by or following a
different trisomy (heterotrisomy). Recurrence of heterotrisomy cannot be accounted for by gonadal mosaicism
in one parent. The risk of recurrence of heterotrisomy
after a T18 index case is low, but in view of the evidence
for predisposition to aneuploidy in younger women
(227), highest risk estimates might be, first, for young
mothers (<30years) who have had an index case with
T18, and a rounded-up 1% at the time of prenatal diagnosis may be offered as the chance of recurrence of any
viable autosomal trisomy. In the case of mothers aged

17

3040years, twice the maternal age-related risk for DS

represents the highest risk; for mothers over 40years, the
maternal-age specific risk of occurrence of trisomy is the
best estimate. Prenatal diagnosis utilizing serum markers
and ultrasound is customarily offered and some families
will desire amniocentesis or chorionic villus sampling
(CVS) for maximum reassurance.
If the T18 phenotype results from a chromosome 18
balanced structural rearrangement present in one parent, the risk of recurrence will almost always be significantly higher, but a more precise risk estimate will
depend on the type of rearrangement and the pattern of
its segregation in the extended family tree.

43.5 TRISOMY 13
In 1960, Patau and coworkers (275) reported T13 syndrome in the same issue of The Lancet that contained
Edwards and colleagues description of T18. That T13
infant had an extra D-group acrocentric chromosome,
microcephaly, anophthalmia/microphthalmia, bilateral
cleft lip and palate, and polydactyly. Notably, she was still
alive at 13 months. The classic T13 syndrome phenotype
was highly distinctive and had almost certainly been the
subject of detailed case reports in earlier centuries (276).

43.5.1 Clinical Diagnosis

A maternal history of severe and/or early-onset preeclampsia may be a prenatal clue to this diagnosis (277).
Pre- or postnatally, the placenta may be recognized as
abnormal or show changes similar to those present in a
partial or mole (278). The mean birth weight is reduced
at 2.6kg. Postaxial polydactyly of the hands and feet plus
any combination of microcephaly, ocular malformation
(anopthalmia/micropthalmia), cleft lip and palate, heart
defect, or renal abnormality is typical (Figure 43-6).
Scalp defects in the region of the posterior fontanelle and
present in nearly 50% of cases, are diagnostically helpful. Cardiac abnormalities, usually septal defects, occur
in over 80% of cases. These defects are rarely the cause
of infant death, that is more likely to be on a central
basis.
Holoprosencephaly is present in about 66% of cases,
with the face malformation (synophthalmia or hypotelorism and premaxillary agenesis) frequently, but not
always, predicting the brain malformation. The cerebral malformation usually comprises a monoventricular
cerebrum without corpus callosum, septum pellucidum,
or fornices. Posterior fossa intracranial abnormalities
with cerebellar malformation and heterotopias, microscopic abnormalities with pyramidal tract hypoplasia,
neural tube defects, and cortical dysplasia are included
among neuropathologic features of T13 that are neither
constant nor obligatory (279). The diagnosis of T13
should always be suspected in an infant with holoprosencephaly and other anomalies. Occasionally the diagnosis

18

CHAPTER 43 Autosomal Trisomies

(a)

(b)

FIGURE 43-6 Trisomy 13. (a) Typical face with bulbous nose and micropthalmia. Note postaxial polydactyly. (b) Typical scalp defects in trisomy 13.
of T13 can be unexpected, as when features of the Potter
sequence obscure the craniofacial findings (personal
experience).
Other pathologic findings in affected fetuses and
infants include atrial and ventricular septal defects with
patent ductus arteriosus, omphalocele, incomplete intestinal rotation or malrotation with unattached mesentery,
enlarged lobulated kidneys with cystic change in the cortex and medulla, accessory spleen, abnormal liver lobation, microscopic pancreatic dysplasia, and changes in
the morphology of the axial skeleton (280).

43.5.2 Prenatal Diagnosis

Prenatal diagnosis of T13 is common and increasingly
cases are diagnosed in utero at 1014weeks on the basis
of ultrasound abnormalities. The most common finding
in the first trimester is increased nuchal edema (281),
with about one-third of fetuses with this presentation
having chromosome abnormalities, chiefly trisomies 21,
18, and 13 and Turner syndrome. Even more predictive
of a chromosome abnormality is cystic hygroma in the
first trimester as about half these fetuses will have chromosome abnormalities. Later in pregnancy hydrops fetalis is relatively common occuring in about 510 of T13
fetuses (282).
Congenital heart disease is seen in over 90% of T13
fetuses and infants, with the most common defects being
ventricular septal defects, atrial septal defects, patent
ductus, hypoplastic aorta, mitral and aortic valve abnormalities, pulmonic stenosis and total anomalous pulmonary venous return. Prenatal detection of these defects
by ultrasound is high, averaging about 50% in multiple
series (282).
Other major birth defects are common in T13 and
can be detected as early as the first trimester. Reviewing

the published series, Chen noted omphalocele in 15%

of fetal T13 and diaphragmatic hernia in 613% (282).
Severe urinary tract malfomations including most commonly hydronephrosis and rarely renal agenesis are
reported in as many as 37% of T13 fetuses. Postaxial
polydactyly seen in about 50% of T13 infants and about
2560% of these anomalies are detected prenatally on
ultrasound. Brain abnormalities, most commonly those
in the holoprosencephaly spectrum, may also be suspected in the first trimester (283,284) and is the most
common abnormality associated with T13. Its presence
in a prenatal sonogram, especially when other abnormalities are documented, is highly suggestive of a diagnosis of T13.

43.5.3 Management
Given the evident seriousness of the malformations present in most affected infants, the immediate management
of newborn infants with T13 and subsequent management of children with T13 raises ethical problems similar
to those encountered in relation to management of T18
or other seriously malformed infants and children (discussed earlier). Median survival in T13 is less than 1week
(7), and more than 80% of affected infants die during
the first month, but about 3% are alive at 6months. If
major congenital heart and renal defects are present,
surgery is usually not undertaken. The issue of cardiac
surgery may become important if the child survives to
23 months and is developing pulmonary hypertension.
One series of nine patients who underwent surgery with
trisomy 18 or 13 found that four of the nine remained
alive at age 2years (285). Individuals surviving to childhood and adulthood with T13 who do not have lifethreatening malformations have profound intellectual
impairment, severe sensory impairments, epilepsy, and

CHAPTER 43 Autosomal Trisomies

feeding difficulties, as well as difficult behaviors such as
self-mutilation (246).
Decisions regarding management need to be made
jointly by care providers and families. These decisions
include whether or not to use oxygen and monitors or
whether or not to consider intervention for cardiac disease. Usually the decision not to treat is considered in the
best interests of the child, but decisions need to be individualized and accompanied by careful counseling (246).

43.5.4 Differential Diagnosis

The overall pattern of anomalies in T13 usually allows
for a rapid clinical diagnosis. There is significant overlap of the major features with other multiple congenital
anomaly syndromes. The presence of postaxial polydactyly may suggest the diagnoses of MeckelGruber
syndrome or Hydrolethalus. Usually the characteristic
internal renal malformations and the presence of encephalocele allow the diagnosis of MeckelGruber and the
brain findings differentiate Hydrolethalus. Another syndrome termed Holoprosencephaly Polydactyly syndrome
is incompletely understood. It is not caused by known
Holoprosencephaly gene mutations (286), but may be an
autosomal recessive condition. A severe presentation of
Smith-Lemli-Opitz symdrome also overlaps significantly
with T13.

43.5.5 Trisomy 13 Mosaicism

Like other mosaic autosomal trisomy phenotypes, mosaic
T13 is variable, from normality to full T13 syndrome
(287,288). As in other trisomies, there is little correlation between the percentage of mosaicism and the clinical phenotype (289). Skin pigment abnormalities such as
hypomelanosis of Ito or the relatively specific phylloid
hypomelanosis (defined as pigmentary mosaicism characterized by congenital hypochromic macules resembling
a floral ornament with various elements such as round
or oval patches, macules resembling the asymmetrical
leaves of a begonia, or oblong lesions) are good clues
(290). Mosaicism for T13 is most often a result of a meiosis I error followed by trisomy rescue (291). Overall,
mosaicism for T13 is quite rare, with only 49 cases being
reported in the most recent published review (292).

43.5.6 Cytogenetics of Trisomy 13

Syndrome
Like trisomies 21 and 18, T13 is a maternal age-related
autosomal trisomy, with the rate at prenatal diagnosis
or birth rising until 43years and then leveling off. About
75% of spontaneous abortuses and the same proportion
of live-born infants with T13 syndrome have an extra,
unattached chromosome 13. SNP arrays and DNA
marker studies have revealed that the extra chromosome

19

is maternally derived in about 90% of these cases (292).

Most of the time the stage of nondisjunction is maternal
meiosis I but in the recent study of Bugge and colleagues
(293) just under half the trisomies were meiosis II errors,
a much higher rate than that seen in the other acrocentric
chromosomes.
In about 20% of cases with T13 syndrome, the extra
chromsome 13 is attached to another chromosome, usually a rob(13q14q), with the greater proportion arising
from new mutations. This translocation carries a significant risk of unbalanced gametes and the segregation in
males reveals more abnormal spermatozoa than previously predicted (294). In addition, in paternal carriers
there is a risk for paternal uniparental disomy (UPD) 14
with a distinct clinical phenotype consisting of characteristic coat hanger rib findings, intellectual disability
and obesity (295,296).
The majority of (13q13q) cases arise de novo and
are isochromosomes arising from prezygotic fusion of
long-arm sister chromatids. Barring effects of isozygosity for a single gene mutation, UPD 13 is expected to be
harmless.

43.5.7 Recurrence Risks

As with T18, recurrence of T13 is rare. In a questionnaire and telephone survey of families with trisomies
18 and 13 children, the sibling recurrence risk was less
than 1% (248,249). As in DS there appears to be a
risk for recurrence that is higher in younger mothers
(212,227). The recurrence risk can be for T13 as well as
other trisomies. Traditionally the highest risk estimates
might be, first, for young mothers less than 30years
who have had an index case with T13; a rounded-up
1% at the time of prenatal diagnosis may be offered
as the chance of recurrence of any viable autosomal
trisomy. In the case of mothers aged 3040years, twice
the maternal age-related risk for DS represents the
highest risk. For mothers over 40years, the maternalage specific risk of occurrence of trisomy is the best
estimate. Cytogenetic prenatal diagnosis is customarily
offered. A recent study by Engels and colleages (297)
suggests that in translocation carriers the risk is probably somewhat higher than the 1% risk previously
estimated. They looked at 101 carriers of a rob 13;14
translocation ascertained in a variety of ways. They
found a miscarriage rate of 27%. Three of 42 amniocentesis in this group revealed T13 (7%). Although not
addressed in this study the risk for paternal UPD 14 is
increased in male carriers.
For male and female carriers of the rob(13q21q) and
rob(13q22q), the risk of T13 syndrome is less than 1%,
but the risk of DS in pregnancies of the female carrier
of rob(13q21q) is 1015%. For the rob(13q15q) carrier,
there is a less than 1% risk for T13, but the significant
risk for UPD 15 is notable.

20

CHAPTER 43 Autosomal Trisomies

REFERENCES
1. Mgarban, A.; Ravel, A.; Mircher, C., etal. The 50th Anniversary of the Discovery of Trisomy 21: The Past, Present,
and Future of Research and Treatment of Down Syndrome.
Genet. Med. 2009, 11, 611616.
2. Resta, R. G. Changing Demographics of Advanced Maternal
Age (AMA) and on the Predicted Incidence of Down Syndrome in the United States: Implications for Prenatal Screening and Genetic Counseling. Am. J. Med. Genet. A 2005,
133A, 3136.
3. Collins, V. R.; Muggli, E. E.; Railey, M. Is Down Syndrome
a Disappearing Birth Defect? J. Pediatr. 2008, 152, 2024.
4. Morris, J. K.; Mutton, D. E.; Alberman, E. Revised Estimates
of the Maternal Age Specific Live Birth Prevalence of Down
Syndrome. J. Med. Screen. 2002, 9, 26.
5. Morris, J. K.; De Vigan, C.; Mutton, D. E.; Alberman, E.
Risk of Down Syndrome Live Birth in Women 35years of
Age and Older. Prenat. Diagn. 2005, 25, 275278.
6. Irving, C.; Richmond, S.; Wren, C., et al. Changes in
Fetal Prevalence and Outcome for Trisomies 13 and 18: A
Population-Based Study over 23 Years. J. Mat. Fet. Neo.
Med. 2011, 24, 137141.
7. Brewer, C. M.; Holloway, S. H.; Stone, D. H., et al. Survival of Trisomy 13 and Trisomy 18 Cases Ascertained from
Population Based Registers. J. Med. Genet. 2002, 39, e54.
8. Root, S.; Carey, J. C. Survival in Trisomy 18. Am. J. Med.
Genet. 1994, 49, 170174.
9. Rasmussen, S. A.; Wong, L. Y.; Yang, Q., etal. PopulationBased Analyses of Mortality in Trisomy 13 and Trisomy 18.
Pediatrics 2003, 111, 777784.
10. Frid, C.; Bjorkhem, G.; Jonzon, A., et al. Long-Term Survival in Children with Atrioventricular Septal Defect and
Common Atrioventricular Valvar Orifice in Sweden. Cardiol. Young 2004, 14, 2431.
11. Esbensen, A. J. Health Conditions Associated with Aging
and End of Life in Adults with Down Syndrome. Int. Rev.
Res. Ment. Retard. 2010, 39, 107126.
12. Bittles, A. H.; Glasson, E. J. Clinical, Social, and Ethical
Implications of Changing Life Expectancy in Down Syndrome. Dev. Med. Child. Neurol. 2004, 46, 282286.
13. Bittles, A. H.; Bower, C.; Hussain, R., et al. The Four
Ages of Down Syndrome. Eur. J. Public Health 2007, 17,
221225.
14. Hunter, A. G. W. Down Syndrome. In Management of
Genetic Syndromes; Cassidy, S. B.; Allanson, J. E., Eds.;
Wiley Blackwell, 2010; pp 309335.
15. Cuniff, C.; Trotter, T. Academy of Pediatrics, Committee on
Genetics, Health Supervision for Children with Down Syndrome. Pediatrics 2001, 108, 442449.
16. Benn, P. A.; Egan, J. F.; Fang, M.; Smith-Bindman, R.
Changes in the Utilization of Prenatal Diagnosis. Obstet.
Gynecol. 2004, 103, 12551260.
17. Ekelund, C. K.; Jorgensen, F. S.; Petersen, O. B., etal. Impact
of a New National Screening Policy for Downs Syndrome
in Denmark: Population Based Cohort Study. BMJ 2009,
338, 449.
18. De Graaf, G.; Haveman, M.; Hochstenbach, R., et al.
Changes in Yearly Birth Prevalence Rates of Children with
Down Syndrome in the Period 19862007 in The Netherlands. JIDR 2011, 112.
19. Skoto, B. G.; Capone, G. T.; Kishnani, P. S. Postnatal
Diagnosis of Down Syndrome: Synthesis of the Evidence
on How Best to Deliver the News. Pediatrics 2009, 124e,
e751e758.
20. Skoto, B. G.; Kishnani, P. S.; Capone, G. T. Prenatal Diagnosis of Down Syndrome: How Best to Deliver the News.
AJMG A 2009, 149A, 23612367.

21. Dent, K. M.; Carey, J. C. Breaking Difficult News in a Newborn Setting: Down Syndrome as a Paradigm, AJMG 142C,
173179.
22. Sheets, K. B.; Chrissman, B. G.; Feist, C. D., etal. Practice
Guidelines for Communicating a Prenatal or Postnatal Diagnosis of Down Syndrome: Recommendations of the National
Society of Genetic Counselors. J. Genet. Couns. 2011,
e751e758.
23. Fenton, L. J. Trisomy 13 and 18 and Quality of Life: Treading Softly. 2011, 155, 15271528.
24. Peters, K. F.; Petrill, S. A. Comparison of the Background,
Needs and Expectations for Genetic Counseling of Adults
with Experience with Down Syndrome, Marfan Syndrome
and Neurofibromatosis. AJMG A 2011, 113.
25. Devlin, L.; Morrison, P. J. Accuracy of the Clinical Diagnosis
of Down Syndrome. Ulster Med. J. 2004, 73, 412.
26. Mutton, D.; Alberman, E.; Hook, E. B. Cytogenetic and
Epidemiological Findings in Down Syndrome, England and
Wales 1989 to 1993, National Down Syndrome Cytogenetic
Register and the Association of Clinical Cytogeneticists.
J. Med. Genet. 1996, 33, 387394.
27. Page, S. L.; Shaffer, L. G. Nonhomologous Robertsonian
Translocations Form Predominantly during Female Meiosis.
Nat. Genet. 1997, 15, 231232.
28. Berend, S. A.; Page, S. L.; Atkinson, W., et al. Obligate
Short-Arm Exchange in de Novo Robertsonian Translocation Formation Influences Placement of Crossovers in Chromosome 21 Nondisjunction. Am. J. Hum. Genet. 2003, 72,
488495.
29. Robinson, W. P.; Bernasconi, F.; Basaran, S., etal. A Somatic
Origin of Homologous Robertsonian Translocations and
Isochromosomes. Am. J. Hum. Genet. 1994, 54, 290302.
30. Devlin, L.; Morrison, P. J. Mosaic Downs Syndrome Prevalence in a Complete Population Study. Arch. Dis. Child.
2004, 89, 11771178.
31. Clarke, C. M.; Edwards, J. H.; Smallpeice, V. 21-Trisomy/
Normal Mosaicism in an Intelligent Child with Some Mongoloid Characters. Lancet 1961, 1, 10281030.
32. De A. Moreira, L.M.; San Juan, A.; Pereira, P. S., de Souza,
C. S. A Case of Mosaic Trisomy 21 with Downs Syndrome
Signs and Normal Intellectual Development. J. Intellect. Disabil. Res. 2000, 44 (Pt 1), 9196.
33. Modi, D.; Berde, P.; Bhartiya, D. Down Syndrome: A Study
of Chromosomal Mosaicism. Reprod. Biomed. Online 2003,
6, 499503.
34. Leon, E.; Zou, Y. S.; Milunsky, J. M. Mosaic Down Syndrome in a Patient with Low-Level Mosaicism Detected by
Microarray. Am. J. Med. Genet. A 2010, 152A, 31543156.
35. Casati, A.; Giorgi, R.; Lanza, A., et al. Trisomy 21 Mosaicism in Two Subjects from Two Generations. Ann. Genet.
1992, 35, 245250.
36. National Institute of Child Health and Human Development
Antenatal Diagnosis: Report of a Consensus Development
Conference; US Department of Health, Education and Welfare, Public Health Service, National Institutes of Health:
Bethesda, 1979.
37. Hagard, S.; Carter, F. A. Preventing the Birth of Infants with
Downs Syndrome: A Cost-Benefit Analysis. BMJ 1976, 1,
753756.
38. Harris, R. A.; Washington, A. E.; Mease, R. F., etal. Cost
Utility of Prenatal Diagnosis and the Risk-Based Threshold.
Lancet 2004, 363, 276282.
39. American College of Obstetricians and Gynecologists Invasive Prenatal Testing for Aneuploidy. ACOG Practice Bulletin; Obstet. Gynecol. 2007, 88 (110), 1459.
40. Canick, J. A.; Kellner, L. H. First Trimester Screening for
Aneuploidy: Serum Biochemical Markers. Semin. Perinatol.
1999, 23, 359368.

CHAPTER 43 Autosomal Trisomies

41. Evans, M. A.; Krantz, D. A.; Hallahan, D. W., etal. MetaAnalysis of First-Trimester Down Syndrome Screening; Free
Beta-Human Gonadotropin Significantly Outperforms Intact
Human Chorionic Gonadotropin in a Multimarker Protocol.
Am. J. Obstet. Gynecol. 2007, 196, 198205.
42. Wald, N. J.; Rodeck, C.; Hackshaw, A. K., etal. First and
Second Trimester Antenatal Screening for Downs Syndrome:
Results of the Serum, Urine and Ultrasound Screening Study
(SURUSS). Health Technol. Assess. 2003, 7, 177.
43. Malone, F. D.; Canick, J. A.; Ball, R. H., etal. First-Trimester
or Second-Trimester Screening, or Both, for Downs Syndrome. N. Engl. J. Med. 2005, 353, 20012011.
44. Nicolaides, K. H. Nuchal Translucency and Other First-
Trimester Sonographic Markers of Chromosomal Abnormalities. Am. J. Obstet. Genecol. 2004, 191, 4567.
45. Schielen, P. C.; Van Leeuwnen-Spreuijt, M.; Belmouden,
I., et al. Multi-Center First-Trimester Screening for Down
Syndrome in The Netherlands in Routine Clinical Practice.
Prenat. Diagn. 2006, 26, 711718.
46. Kagan, K. O.; Wright, D.; Valencia, C., etal. Screening for
Trisomies 21, 18 and 13 by Maternal Age, Fetal Nuchal
Translucency, Fetal Heart Rate, Free Beta-hCG and Pregnancy Associated-Plasma Protein-A. Human Reprod. 2008,
23, 19681975.
47. Molina, F. S.; Avgidou, K.; Kagan, K. O., et al. Cystic
Hygromas, Nuchal Edema and Nuchal Translucency at
114 Weeks of Gestation. Obstet. Gynecol. 2006, 107,
678683.
48. Nicolaides, K. H. First Trimester Screening for Chromosomal Abnormalities. Semin. Perinatol. 2005, 29, 190194.
49. Ball, R. H.; Caughey, A. B.; Malone, F. D., etal. First- and
Second-Trimester Evaluation of Risk for Down Syndrome.
Obstet. Gynecol. 2007, 110, 1017.
50. Breathnach, F. M.; Fleming, A.; Malone, F. D. The Second
Trimester Genetic Sonogram. Am. J. Med. Genet. C Semin.
Med. Genet. 2007, 145 C, 6272.
51. Simpson, J. M.; Cook, A.; Sharland, G. The Significance
of Echogenic Foci in the Fetal Heart: A Prospective Study
of 228 Cases. Ultrasound Obstet. Gynecol. 1996, 8, 225
228.
52. Shanks, A. L.; Odibo, A. O.; Gray, D. L. Echogenic Intracardiac Foci: Associated with Increased Risk for Fetal
Trisomy 21 or Not? J. Ultrasound Med. 2009, 28 (12),
16391643.
53. Anderson, N.; Jyoti, R. Relationship of Isolated Fetal Intracardiac Echogenic Focus to Trisomy 21 at the Mid Trimester
Sonogram in Women Younger Than 35years. Ultrasound
Obstet. Gynecol. 2003, 21, 354358.
54. Coco, C.; Jeanty, P. Karyotyping of Fetus with Isolated Choroid Plexus Cysts is Not Justified in an Unselected Population. J. Ultrasound Med. 2004, 23, 899906.
55. Bethune, M. Time to Reconsider Our Approach to Echogenic Intracardiac Focus and Choroid Plexus Cysts. Aust. N.
Z. J. Obstet. Gynaecol. 2008, 48 (2), 137141.
56. Cicero, S.; Avgidou, K.; Rembouskos, G., etal. Nasal Bone
in First-Trimester Screening for Trisomy 21. Amer. J. Obstet.
Genecol. 2006, 195, 109114.
57. Smith-Bindman, R.; Hosmer, W.; Feldstein, V. A., et al.
Second-Trimester Ultrasound to Detect Fetuses with
Down Syndrome: A Meta-Analysis. JAMA 2001, 285,
10441055.
58. Smith-Bindman, R.; Chu, P.; Goldberg, J. D. Second Trimester Prenatal Ultrasound with the Detection of Pregnancies at
Increased Risk of Down Syndrome. Prenat. Diagn. 2007, 27,
535544.
59. Bahado-Singh, R. O.; Choi, S. J.; Oz, U., etal. Early SecondTrimester Individualized Estimation of Trisomy 18 Risk by
Ultrasound. Obstet. Gynecol. 2003, 101, 463468.

21

60. Oyelese, Y.; Vintzileos, A. M. Is Second-Trimester Genetic

Amniocentesis for Trisomy 18 Ever Indicated in the Presence
of a Normal Genetic Sonogram? Ultrasound Obstet. Gynecol. 2005, 26, 691694.
61. Papageorghiou, A. T.; Avgidou, K.; Spencer, K., et al.
Sonographic Screening for Trisomy 13 at 11 to 13 (+6)
Weeks of Gestation. Am. J. Obstet. Gynecol. 2006, 194,
397401.
62. Van Lith, J. M.; Benacerraf, B. R.; Yagel, S. Current Controversies in Prenatal Diagnosis 2: Down Syndrome Screening:
Is Ultrasound Better Than Cell-Free Ncleic Acids in Maternal
Blood? Prenat. Diagn. 2011, 31, 231234.
63. Lun, F. M.; Jin, Y. Y.; Sun, H., etal. Noninvasive Prenatal
Diagnosis of a Case of Down Syndrome due to Robertsonian
Translocation by Massively Parallel Sequencing of Maternal
Plasma DNA. Letters to the Editor; Clin. Chem. 2011, 57,
917919.
64. Hahn, S.; Lapaire, O.; Tercanli, S., et al. Determination of
Fetal Chromosome Aberrations from Fetal DNA in Maternal Blood: Has the Challenge Finally Been Met? Expert Rev.
Mol. Med. 2011, 13, e16.
65. Jain, S.; Agarwal, S.; Panigrahi, I., etal. Diagnosis of Down
Syndrome and Detection of Origin of Nondisjunction by
Short Tandem Repeat Analysis. Genet. Test. Mol. Biomarkers 2010, 14, 489491.
66. Fried, K. A Score Based on Eight Signs in the Diagnosis of
Down Syndrome in the Newborn. J. Ment. Defic. Res. 1980,
24, 181185.
67. Christianson, A. L. Down Syndrome in Black South African
Infants and ChildrenClinical Features and Delayed Diagnosis. S. Afr. Med. J. 1997, 87, 992995.
68. Christianson, A. L.; Kromberg, J. G. Maternal Non-
Recognition of Down Syndrome in Black South African
Infants. Clin. Genet. 1996, 49, 141144.
69. Jones, K. L. Down Syndrome, Smiths Recognizable Patterns
of Human Malformation, 6th ed.; Elsevier Saunders: Philadelphia, 2006, 7.
70. Farkas, L. G.; Katic, M. J.; Forrest, C. R. Age-Related
Changes in Anthropometric Measurements in the Craniofacial Regions and in Height in Downs Syndrome. J. Craniofac. Surg. 2002, 13, 614622.
71. Hindley, D.; Medakkar, S. Diagnosis of Downs Syndrome
in Neonates. Arch. Dis. Child. Fetal Neonatal Ed. 2002, 87,
F220FF21.
72. Horn, D.; Neitzel, H.; Tonnies, H., etal. Familial MCA/MR
Syndrome due to Inherited Submicroscopic Translocation
t(18;21) (q22.1-q21.3) with Breakpoint at the Down Syndrome Critical Region. Am. J. Med. Genet. A 2003, 117,
236244.
73. Stewart, D. R.; Huang, A.; Faravelli, F., etal. Subtelomeric
Deletions of Chromosome 9q: A Novel Microdeletion Syndrome. Am. J. Med. Genet. A 2004, 128A, 340351.
74. Rasmussen, P.; Borjesson, O.; Wentz, E.; Gillberg, C. Autistic Disorders in Down Syndrome: Background Factors and
Clinical Correlates. Dev. Med. Child. Neurol. 2001, 43,
750754.
75. Visootsak, J.; Sherman, S. Neuropsychiatric and Behavioral
Aspects of Trisomy 21. Curr. Psychiatry Rep. 2007, 9 (2),
135140.
76. Di Nuovo, S.; Buono, S. Behavioral Phenotypes of Genetic
Syndromes with Intellectual Disability: Comparison of Adaptive Profiles. Psychiatry Res. 2011, Epub ahead of print.
77. Antonarakis, S. E.; Epstein, C. J. The Challenge of Down
Syndrome. Trends Mol. Med. 2006, 12, 473479.
78. Mrak, R. E.; Griffin, W. S. Trisomy 21 and the Brain. J. Neuropathol. Exp. Neurol. 2004, 63, 679685.
79. Nadel, L. Downs Syndrome: A Genetic Disorder in Biobehavioral Perspective. Genes Brain Behav. 2003, 2, 156166.

22

CHAPTER 43 Autosomal Trisomies

80. Pennington, B. F.; Moon, J.; Edgin, J., etal. The Neuropsychology of Down Syndrome: Evidence for Hippocampal
Dysfunction. Child Dev. 2003, 74, 7593.
81. Brown, F. R., 3rd; Greer, M. K.; Aylward, E. H.; Hunt,
H. H. Intellectual and Adaptive Functioning in Individuals
with Down Syndrome in Relation to Age and Environmental
Placement. Pediatrics 1990, 85, 450452.
82. Roizen, N. J.; Patterson, D. Downs Syndrome. Lancet 2003,
361, 12811289.
83. Lott, I. T.; Dierssen, M. Cognitive Deficits and Associated
Neurological Complications in Individuals with Downs
Syndrome. Lancet Neurol. 2010, 9, 623633.
84. Abbeduto, L.; Warren, S.; Conners, F. A. Language Development in Down Syndrome: From the Prelinguistic Period
to the Acquisition of Literacy. Mental Retard. Dev Disabil.
2007, 13, 247261.
85. Chapman, R. S.; Schwartz, S. E.; Bird, E. K. Language Skills
of Children and Adolescents with Down Syndrome: I Comprehension. J. Speech Hear. Res. 1991, 34, 11061120.
86. Epstein, C. J. Down Syndrome (Trisomy 21). In The Metabolic and Molecular Basis of Inherited Disease, 8th ed.;
Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D., Eds.;
McGraw-Hill: New York, 2001; pp 749794.
87. Zigman, W. B.; Lott, I. T. Alzheimers Disease in Down Syndrome: Neurobiology and Risk. Mental Retard. Dev. Disabil. 2007, 13, 237246.
88. Madan, V.; Williams, J.; Lear, J. T. Dermatological Manifestations of Down Syndrome. Clin. Exp. Dermatol. 2006, 31,
623629.
89. Pueschel, S. M.; Rothman, K. J.; Ogilby, J. D. Birth Weight
of Children with Downs Syndrome. Am. J. Ment. Defic.
1976, 80, 442445.
90. Toledo, C.; Alembik, Y.; Aguirre Jaime, A.; Stoll, C. Growth
Curves of Children with Down Syndrome. Ann. Genet.
1999, 42, 8190.
91. Cronk, C.; Crocker, A. C.; Pueschel, S. M., et al. Growth
Charts for Children with Down Syndrome: 1Month to 18
Years of Age. Pediatrics 1988, 81, 102110.
92. Myrelid, A.; Gustafsson, J.; Ollars, B.; Anneren, G. Growth
Charts for Downs Syndrome from Birth to 18 Years of Age.
Arch. Dis. Child. 2002, 87, 97103.
93. Cremers, M. J.; Van der Tweel, I.; Boersma, B., etal. Growth
Curve of Dutch Children with Downs Syndrome. J. Intellect. Disabil. Res. 1996, 40 (Pt 5), 412420.
94. Mequid, N. A.; El-Kotoury, A. I.; Abdel-Salam, G. M.,
etal. Growth Charts of Egyptian Children with Down Syndrome (036Months). East Meditrerr. Health J. 2004, 10,
106115.
95. Rosenbloom, S. T.; McGregor, T. L.; Chen, Q., etal. Specialized Pediatric Grown Charts For Electronic Health Record
Systems: The Example of Down Syndrome. AMIA 2010
Symp. Proc. 2010, 687691.
96. Murray, J.; Ryan-Krause, P. Obesity in Children with Down
Syndrome: Background and Recommendations for Management. Pediatr. Nurs. 2010, 36, 314319.
97. Patel, B. N.; Pang, D.; Stern, Y., et al. Obesity Enhances
Verbal Memory in Postmenopausal Women with Down Syndrome. Neurobiol. Aging 2004, 25, 159166.
98. Andriolo, R.; El Dib, R.; Ramos, L. Aerobic Exercise Training Programmes for Improving Physical and Psychosocial
Health in Adults with Down Syndrome. Cochrane Database
Syst. Rev. 2005, 5, CD005176.
99. Angelopoulou, N.; Souftas, V.; Sakadamis, A., et al. Bone
Mineral Density in Adults with Downs Syndrome. Eur.
Radiol. 1999, 9, 648651.
100. Sakadamis, A.; Angelopoulou, N.; Matziari, C., etal. Bone
Mass, Gonadal Function and Biochemical Assessment in
Young Men with Trisomy 21. Eur. J. Obstet. Gynecol.
Reprod. Biol. 2002, 100, 208212.

101. Mtt, T.; Mtt, J.; Tervo-Mtt, T., etal. Healthcare

and Guidelines: A Population-Based Survey of Recorded
Medical Problems and Health Surveillance for People
with Down Syndrome. J. Intellect. Dev. Disabil. 2011, 36,
118126.
102. Book, L.; Hart, A.; Black, J., etal. Prevalence and Clinical
Characteristics of Celiac Disease in Downs Syndrome in a US
Study. Am. J. Med. Genet. 2001, 98, 7074.
103. Anneren, G.; Gustavson, K. H.; Sara, V. R., et al. Growth
Retardation in Down Syndrome in Relation to Insulin-Like
Growth Factors and Growth Hormone. Am. J. Med. Genet.
Suppl. 1990, 7, 5962.
104. Anneren, G.; Tuvemo, T.; Carlsson-Skwirut, C., etal. Growth
Hormone Treatment in Young Children with Downs Syndrome: Effects on Growth and Psychomotor Development.
Arch. Dis. Child. 1999, 80, 334338.
105. Anneren, G.; Tuvemo, T.; Gustafsson, J. Growth Hormone
Therapy in Young Children with Down Syndrome and a
Clinical Comparison of Down and PraderWilli Syndromes.
Growth Horm. IGF Res. 2000, 10 (Suppl. B), S87S89.
106. Myrelid, A.; Frisk, P.; Stridsberg, M., etal. Normal Growth
Hormone Secretion in Overweight Young Adults with Down
Syndrome. Growth Horm. IGF Res. 2010, 20, 174178.
107. Freeman, S. B.; Taft, L. F.; Dooley, K. J., etal. PopulationBased Study of Congenital Heart Defects in Down Syndrome. Am. J. Med. Genet. 1998, 80, 213217.
108. Geggel, R. L.; OBrien, J. E.; Feingold, M. Development of
Valve Dysfunction in Adolescents and Young Adults with
Down Syndrome and No Known Congenital Heart Disease.
J. Pediatr. 1993, 122, 821823.
109. Hamada, T.; Gejyo, F.; Koshino, Y., etal. Echocardiographic
Evaluation of Cardiac Valvular Abnormalties in Adults with
Downs Syndrome. Tohoku J. Exp. Med. 1998, 185, 3135.
110. Mathias, M. F.; Simionato, M. R.; Guar, R. O. Some Factors Associated with Dental Caries in the Primary Dentition
of Children with Down Syndrome. Eur. J. Paediatr. Dent.
2011, 12, 3742.
111. Yoshihara, T.; Morinushi, T.; Kinjyo, S.; Yamasaki, Y.
Effect of Periodic Preventive Care on the Progression of Periodontal Disease in Young Adults with Downs Syndrome. J.
Clin. Periodontol. 2005, 32, 556560.
112. Dunlop, K. A.; Mulholland, H. C.; Casey, F. A., et al. A
Ten Year Review of Atrioventricular Septal Defects. Cardiol.
Young 2004, 14, 1523.
113. Kabbani, M. S.; Giridhar, S.; Elbarbary, M., etal. Postoperative Cardiac Intensive Care Outcome for Down Syndrome
Children. Saudi Med. J. 2005, 26, 943946.
114. Lindberg, L.; Olsson, A. K.; Jogi, P.; Jonmarker, C. How
Common is Severe Pulmonary Hypertension after Pediatric
Cardiac Surgery? J. Thorac. Cardiovasc. Surg. 2002, 123,
11551163.
115. Shah, P. S.; Hellmann, J.; Adatia, I. Clinical Characteristics
and Follow Up of Down Syndrome Infants without Congenital Heart Disease Who Presented with Persistent Pulmonary Hypertension of Newborn. J. Perinat. Med. 2004, 32,
168170.
116. Raina, T.; McGrath, E.; Gunn, J. Myocardial Infarction in a
Patient with Down Syndrome: A Case Report and Review of
the Literature. Clin. Cardiol. 2011, 34, 8789.
117. Khocht, A.; Janal, M.; Turner, B. Periodontal Health in
Down Syndrome: Contributions of Mental Disability, Personal, and Professional Dental Care. Spec. Care Dentist.
2010, 3, 118123.
118. Fabia, J.; Drolette, M. Malformations and Leukemia in Children with Down Syndrome. Pediatrics 1970, 45, 6070.
119. Freeman, S. B.; Torfs, C. P.; Romitti, P. A., etal. Congenital
Gastrointestinal Defects in Down Syndrome: A Report from
the Atlanta and National Down Syndrome Projects. Clin.
Genet. 2009, 75, 180184.

CHAPTER 43 Autosomal Trisomies

120. Singh, M. V.; Richards, C.; Bowen, J. C. Does Down Syndrome Affect the Outcome of Congenital Duodenal Obstruction? Pediatr. Surg. Int. 2004, 20, 586589.
121. Ieiri, S.; Higashi, M.; Teshiba, R. Clinical Features of
Hirschsprungs Disease Associated with Down Syndrome: A
30-Year Retrospective Nationwide Survey in Japan. J. Pediatr. Surg. 2009, 44, 23472351.
122. Hackam, D. J.; Reblock, K.; Barksdale, E. M., et al. The
Influence of Downs Syndrome on the Management and
Outcome of Children with Hirschsprungs Disease. J. Pediatr. Surg. 2003, 38, 946949.
123. Cleves, M. A.; Hobbs, C. A.; Cleves, P. A., et al. Congenital Defects among Liveborn Infants with Down Syndrome. Birth Defects Res. A Clin. Mol. Teratol. 2007, 79,
657666.
124. Zarate, N.; Mearin, F.; Hidalgo, A.; Malagelada, J. R.
Prospective Evaluation of Esophageal Motor Dysfunction in Downs Syndrome. Am. J. Gastroenterol. 2001, 96,
17181724.
125. Henderson, A.; Lynch, S. A.; Wilkinson, S., etal. Adults with
Downs Syndrome: The Prevalence of Complications and
Health Care in the Community. Br. J. Gen. Pract. 2007, 57,
5055.
126. Wallace, R. A. Clinical Audit of Gastrointestinal Conditions
Occurring among Adults with Down Syndrome Attending a Specialist Clinic. J. Intellect. Dev. Disabil. 2007, 32,
4550.
127. Carlsson, A. K.; Axelsson, I. E.; Borulf, S. K., et al. Serological Screening for Celiac Disease in Healthy 2.5-Year-Old
Children in Sweden. Pediatrics 2001, 107, 4245.
128. Cohen, W. I. Current Dilemmas in Down Syndrome Clinical
Care: Celiac Disease, Thyroid Disorders, and Atlanto-Axial
Instability. Am. J. Med. Genet. C Semin. Med. Genet. 2006,
142C, 141148.
129. Hill, I.; Dirks, M.; Liptak, G., etal. Guidelines for the Diagnosis and Treatment of Celiac Disease in Children; Recommendations of the North American Society for Pediatric
Gastroenterology, Hepatology and Nutrition. J. Pediatr.
Gastroenterol. 2005, 40, 119.
130. Shott, S. R. Down Syndrome: Common Otolaryngologic
Manifestations. 2006, 142C, 131140.
131. Shott, S. R.; Joseph, A.; Heithaus, D. Hearing Loss in Children with Down Syndrome. Int. J. Pediatr. Otorhinolaryngol. 2001, 61, 199205.
132. Venail, F.; Gardiner, Q.; Mondain, M. ENT and Speech Disorders in Children with Downs Syndrome: An Overview of
Pathophysiology, Clinical Features, Treatments, and Current
Management. Clin. Pediatr. (Phila) 2004, 43, 783791.
133. Donnelly, L. F.; Shott, S. R.; LaRose, C. R., etal. Causes of
Persistent Obstructive Sleep Apnea Despite Previous Tonsillectomy and Adenoidectomy in Children with Down Syndrome as Depicted on Static and Dynamic Cine MRI. AJR
Am. J. Roentgenol. 2004, 183, 175181.
134. Dyken, M. E.; Lin-Dyken, D. C.; Poulton, S., etal. Prospective Polysomnographic Analysis of Obstructive Sleep Apnea
in Down Syndrome. Arch. Pediatr. Adolesc. Med. 2003,
157, 655660.
135. Erler, T.; Paditz, E. Obstructive Sleep Apnea Syndrome in
Children: A State-of-the-Art Review. Treat. Respir. Med.
2004, 3, 107122.
136. Kim, J. H.; Hwang, J. M.; Kim, H. J.; Yu, Y. S. Characteristic Ocular Findings in Asian Children with Down Syndrome.
Eye 2002, 16, 710714.
137. Creavin, A. L.; Brown, R. D. Opthalmic Abnormalities in
Children with Down Syndrome. J. Pediatr. Ophthalmol.
Strabismus. 2009, 46, 7682.
138. Coats, D. K.; McCreery, K. M.; Plager, D. A., etal. Nasolacrimal Outflow Drainage Anomalies in Downs Syndrome.
Ophthalmology 2003, 110, 14371441.

23

139. Stoiber, J.; Muss, W.; Ruckhofer, J.; Grabner, G. Acute

Keratoconus with Perforation in a Patient with Downs Syndrome. Br J Ophthalmol 2003, 87, 120.
140. Stephen, E.; Dickson, J.; Kindley, A. D. Surveillance of
Vision and Ocular Disorders in Children with Down Syndrome. Dev. Med. Child. Neurol. 2007, 49, 513515.
141. Henry, E.; Walker, D.; Wiedmeier, S. E., et al. Hematological Abnormalities during the First Week of life Among
Neonates with Down Syndrome: Data from a Multihospital
Healthcare System. Am. J. Med. Genet. A 2007, 143, 4250.
142. Kirsammer, G.; Jilani, S.; Liu, H., et al. Highly Penetrant
Myeloproliferative Disease in the Ts65Dn Mouse Model of
Down Syndrome. Blood 2008, 111, 767775.
143. Lorenzo, L. P.; Chen, H.; Shatynski, K. E. Defective Hematopoietic Stem Cell and Lymphoid Progenitor Development
in the Ts65Dn Mouse Model of Down Syndrome: Potential
Role of Oxidative Stress. Antioxid. Redox. Signal. 2011 Jun
15, Epub ahead of print.
144. Ng, A. P.; Loughran, S. J.; Metcalf, D., etal. ERQG is Required
for Self-Renewal of Hematopoietic Stem Cells during Stress
Hematopoiesis in Mice. Blood 2011, Epub ahead of print.
145. Anuk, D.; Tarcan, A.; Alioglu, B., etal. Hydrops Fetalis in
a Neonate with Down Syndrome, Transient Myeloproliferative Disorder and Hepatic Fibrosis. Fetal Pediatr. Pathol.
2007, 26, 223228.
146. Zipursky, A. Transient Leukaemiaa Benign Form of Leukaemia in Newborn Infants with Trisomy 21. Br. J. Haematol. 2003, 120, 930938.
147. Zwaan, C. M.; Reinhardt, D.; Hitzler, J., etal. Acute Leukemias in Children with Down Syndrome. Hematol. Oncol.
Clin. North Am. 2010, 24, 1934.
148. Burch, J. M.; Weston, W. L.; Rogers, M.; Morelli, J. G.
Cutaneous Pustular Leukemoid Reactions in Trisomy 21.
Pediatr. Dermatol. 2003, 20, 232237.
149. Piersigilli, F.; Diociaiuti, A.; Boldrini, R., etal. Vesiculopustular Eruption in a Neonate with Trisomy 21 Syndrome as a
Clue of Transient Myeloproliferative Disorders. Cutis 2010,
85, 286288.
150. Xavier, A. C.; Ge, Y.; Taub, I., etal. Unique and Biological
Features of Leukemia in Down Syndrome Children. Expert
Rev. Hematol. 2010, 3, 175186.
151. Dormann, S.; Kruger, M.; Hentschel, R., et al. Life-
Threatening Complications of Transient Abnormal Myelopoiesis in Neonates with Down Syndrome. Eur. J. Pediatr.
2004, 163, 374377.
152. Webb, D. K. Optimizing Therapy for Myeloid Disorders of
Down Syndrome. Br. J. Haematol. 2005, 131, 37.
153. Al-Kasim, F.; Doyle, J. J.; Massey, G. V., etal. Incidence and
Treatment of Potentially Lethal Diseases in Transient Leukemia of Down Syndrome: Pediatric Oncology Group Study. J.
Pediatr. Hematol. Oncol. 2002, 24, 913.
154. Muramatsu, H.; Kato, K.; Watanabe, N., et al. Risk Factors for Early Death in Neonates with Down Syndrome and
Transient Leukemia. Br. J. Haematol. 2008, 142, 610615.
155. Massey, G. V.; Zipursky, A.; Chang, M. N., et al. A Prospective Study of the Natural History of Transient Leukemia (TL) in Neonates with Down Syndrome (DS): Childrens
Oncology Group (COG) Study POG-9481. Blood 2006,
107, 46064613.
156. Malinge, S.; Izraeli, S.; Crispino, J. D. Insights into the Manifestations, Outcomes, and Mechanisms of Leukemogenesis
in Down Syndrome. Blood 2009, 113, 26192628.
157. Taub, J. W.; Munschau, G.; Ge, Y., etal. Prenatal Origin of
GATA1 Mutations May Be an Initiating Step in the Development of Megakaryocytic Leukemia in Down Syndrome.
Blood 2004, 104, 15881589.
158. Pine, S. R.; Guo, Q.; Yin, C., et al. Incidence and Clinical
Implications of GATA1 Mutations in Newborns with Down
Syndrome. Blood 2007, 110, 21282131.

24

CHAPTER 43 Autosomal Trisomies

159. Alford, K. A.; Reinhardt, K.; Garnett, C. Analysis of GATA1

Mutations in Down Syndrome Transient Myeloproliferative
Disorder and Myeloid Leukemia. Blood 2011 Jun 29, Epub
ahead of print.
160. De Vita, S.; Canzonetta, C.; Mulligan, C., et al. Trisomic
Dose of Several Chromosome 21 Genes Perturbs Haematopoietic Stem and Progenitor Cell Differentiation in Downs
Syndrome. Oncogene 2010, 29, 61026114.
161. Kanezaki, R.; Toki, T.; Terui, K., etal. Down Syndrome and
GATA1 Mutations in Transient Abnormal Myeloproliferative Disorder: Mutation Classes Correlate with Progression
to Myeloid Leukemia. Blood 2010, 116, 46314638.
162. Chessels, J. M.; Harrison, G.; Richards, S. M., etal. Downs
Syndrome and Acute Lymphoblastic Leukaemia: Clinical Features and Response to Treatment. Arch. Dis. Child.
2001, 85, 321353.
163. Whitlock, J. A. Down Syndrome and Acute Lymphoblastic
Leukaemia. Br. J. Haematol. 2006, 135, 595602.
164. Ram, G.; Chinen, J. Infections and Immunodeficiency in
Down Syndrome. Clin. Exp. Immunol. 2011, 164, 916.
165. Bloemers, B. L.; Van Bleek, G. M.; Kimpen, J. L.; Bont, L.
Distinct Abnormalities in the Innate Immune System of Children with Down Syndrome. J. Pediatr. 2010, 156, 804809.
166. Verstegen, R. H.; Kusters, M. A.; Gemen, E. F., etal. Down
Syndrome B-Lymphocyte Subpopulations, Intrinsic Defect
or Decreased T-Lymphocyte Help. Pediatr. Res. 2010, 67,
563569.
167. Joshi, A. Y.; Abraham, R. S.; Snyder, M. R., etal. Immune
Evaluation and Vaccine Responses in Down Syndrome: Evidence of Immunodeficiency? Vaccine 2011, 29, 50405046.
168. Kusters, M. A.; Verstegen, R. H.; Gemen, E. F., etal. Intrinsic Defect of the Immune System in Children with Down Syndrome: A Review. Clin. Exp. Immunol. 2009, 156, 189193.
169. Bloemers, B. L.; Bont, L.; de Weger, R. A., etal. Decreased
Thymic Output Accounts for Decreased Naive T Cell Numbers in Children with Down Syndrome. J. Immunol. 2011,
186, 45004507.
170. Van Trotsenburg, A. S.; Vulsma, T.; van Santen, H. M.,
etal. Lower Neonatal Screening Thyroxine Concentrations
in Down Syndrome Newborns. J. Clin. Endocrinol. Metab.
2003, 88, 15121515.
171. Van Trotsenburg, A. S.; Vulsma, T.; Rutgers van
Rozenburg-Marres, S. L., et al. The Effect of Thyroxine
Treatment Started in the Neonatal Period on Development
and Growth of Two Years Old Down Syndrome Children:
A Randomized Clinical Trial. J. Clin. Endocrinol. Metab.
2005, 90, 33043311.
172. Gibson, P. A.; Newton, R. W.; Selby, K., etal. Longitudinal
Study of Thyroid Function in Downs Syndrome in the First
Two Decades. Arch. Dis. Child. 2005, 90, 574578.
173. Prasher, V.; Ninan, S.; Haque, S. Fifteen-Year Follow-Up of
Thyroid Status in Adults with Down Syndrome. J. Intellect.
Disabil. Res. 2011, 55, 392396.
174. Anwar, A. L.; Walker, J. D.; Frier, B. M. Type 1 Diabetes Mellitus and Downs Syndrome: Prevalence, Management and Diabetic Complications. Diabet. Med. 1998, 15,
160163.
175. Rohrer, T. R.; Hennes, P.; Thon, A. Downs Syndrome in
Diabetic Patients Aged <20years: An Analysis of Metabolic Status, Glycaemic Control and Autoimmunity in
Comparison with Type 1 Diabetes. Diabetologia 2010, 53,
10701075.
176. Fonseca, C. T.; Amaral, D. M.; Ribeiro, M. G., etal. Insulin
Resistance in Adolescents with Down Syndrome: A CrossSectional Study. BMC Endocr. Disord. 2005, 5, 56.
177. Ejsskjaer, K.; Uldbjerg, N.; Goldstein, H. Menstrual Profile
and Early Menopause in Women with Down Syndrome Aged
2640years. J. Intellect. Dev. Disabil. 2006, 31, 166171.

178. Hankinson, T.C.; Anderson, R.C. Craniovertebral Junction

Abnormalities in Down Syndrome. 2010, 66, 66326638.
179. Morton, R. E.; Khan, M. A.; Murray-Leslie, C., etal. Antlantoaxial Instability in Downs Syndrome: A Five Year Follow Up Study. Arch. Dis.Child. 1995, 72, 115118.
180. Wellborn, C. C.; Sturm, P. F.; Hatch, R. S., et al. Intraobserver Reproducibility and Interobserver Reliability of Cervical Spine Measurements. J. Pediatr. Orthop. 2000, 20,
6670.
181. Arya, R.; Kabra, M.; Gulati, S. Epilepsy in Children with
Down Syndrome. Epileptic Disord. 2011, 13, 17.
182. Menndez, M. Down Syndrome, Alzheimers Disease and
Seizures. Brain Dev. 2005, 27, 246252.
183. De Simone, R.; Puig, X. S.; Glisse, P., et al. Senile Myoclonic Epilepsy: Delineation of a Common Condition Associated with Alzheimers Disease in Down Syndrome. Brain
Dev. 2010, 19, 383389.
184. Patel, A.; Rees, S. D.; Kelly, M. A., et al. Association of
Variants within APOE, SORL1, RUNX1, BACE1 and
ALDH18A1 with Dementia in Alzheimers Disease in Subjects with Down Syndrome. Neurosci. Lett. 2011, 487,
144148.
185. Iqbal, K.; Liu, F.; Gong, C. X., et al. Mechanisms of TauInduced Neurodegeneration. Acta Neuropathol. 2009, 118,
5369.
186. Gyure, K. A.; Durham, R.; Stewart, W. F., et al. Intraneuronal Abeta-Amyloid Precedes Development of Amyloid
Plaques in Down Syndrome. Arch. Pathol. Lab. Med. 2001,
125, 489492.
187. Head, E.; Lott, I. T. Down Syndrome and Beta-Amyloid
Deposition. Curr. Opin. Neurol. 2004, 17, 95100.
188. Johnson, N.; Fahey, C.; Chicoine, B., etal. Effects of Donepezil on Cognitive Functioning in Down Syndrome. Am. J.
Ment. Retard. 2003, 108, 367372.
189. Hassold, T.; Sherman, S. Down Syndrome: Genetic Recombination and the Origin of the Extra Chromosome 21. Clin.
Genet. 2000, 57, 95100.
190. Hultn, M. A.; Patel, S. D.; Westgren, M., etal. On the Paternal Origin of Trisomy 21 Down Syndrome. Mol. Cytogenet.
2010, 23, 34.
191. Bruyere, H.; Rupps, R.; Kuchinka, B. D., et al. Recurrent
Trisomy 21 in a Couple with a Child Presenting Trisomy 21
Mosaicism and Maternal Uniparental Disomy for Chromosome 21 in the Euploid Cell Line. Am. J. Med. Genet. 2000,
94, 3541.
192. Hassold, T. J.; Burrage, L. C.; Chan, E. R., etal. Maternal
Folate Polymorphisms and the Etiology of Human Nondisjunction. Am. J. Hum. Genet. 2001, 69, 434439.
193. Hunt, P. A.; Hassold, T. J. Sex Matters in Meiosis. Science
2002, 296, 21812183.
194. Lamb, N. E.; Hassold, T. J. Nondisjunctiona View from
Ringside. N. Engl. J. Med. 2004, 351, 19311934.
195. Lamb, N. E.; Yu, K.; Shaffer, J., etal. Association between
Maternal Age and Meiotic Recombination for Trisomy 21.
Am. J. Hum. Genet. 2005, 76, 9199.
196. Lacefield, S.; Murray, A. A Delay Like No Other. Nat.
Genet. 2005, 37, 662663.
197. De Medina-Redondo, M.; Meraldi, P. The Spindle Assembly
Checkpoint: Clock or Domino? Results Probl. Cell Differ.
2011, 53, 7591.
198. Carothers, A. D.; Castilla, E. E.; Dutra, M. G., etal. Search
for Ethnic, Geographic and Other Factors in the Epidemiology of Down Syndrome in South America: Analysis of Data
from the ECLAMC Project, 19671997. Am. J. Med. Genet.
2001, 103, 149156.
199. Botto, L. D.; Mulinare, J.; Yang, Q., et al. Autosomal
Trisomy and Maternal Use of Multivitamin Supplements.
Am. J. Med. Genet. A 2004, 125, 113116.

CHAPTER 43 Autosomal Trisomies

200. Christianson, R. E.; Sherman, S. L.; Torfs, C. P. Maternal
Meiosis II Nondisjunction in Trisomy 21 is Associated with
Maternal Low Socioeconomic Status. Genet. Med. 2004, 6,
487494.
201. Doria-Rose, V. P.; Kim, H. S.; Augustine, E. T.; Edwards,
K. L. Parity and the Risk of Downs Syndrome. Am. J. Epidemiol. 2003, 158, 503508.
202. Kline, J.; Kinney, A.; Levin, B.; Warburton, D. Trisomic
Pregnancy and Earlier Age at Menopause. Am. J. Hum.
Genet. 2000, 67, 395404.
203. Kline, J.; Kinney, A.; Reuss, M. L., et al. Trisomic Pregnancy and the Oocyte Pool. Hum. Reprod. 2004, 19,
16331643.
204. Freeman, S. B.; Yang, Q.; Allran, K., etal. Women with a
Reduced Ovarian Complement May Have an Increased
Risk for a Child with Down Syndrome. Am. J. Hum. Genet.
2000, 66, 16801683.
205. Schon, E. A.; Kim, S. H.; Ferreira, J. C., et al. Chromosomal Non-Disjunction in Human Oocytes: Is There a Mitochondrial Connection? Hum. Reprod. 2000, 15 (Suppl. 2),
160172.
206. Hobbs, C. A.; Cleves, M. A.; Lauer, R. M., etal. Preferential
Transmission of the MTHFR 677 T Allele to Infants with
Down Syndrome: Implications for a Survival Advantage.
Am. J. Med. Genet. 2002, 113, 914.
207. Barkai, G.; Arbuzova, S.; Berkenstadt, M., etal. Frequency
of Downs Syndrome and Neural-Tube Defects in the Same
Family. Lancet 2003, 361, 13311335.
208. Olsen, J. H.; Winther, J. F. Downs Syndrome and Neural
Tube Defects in the Same Families. Lancet 2003, 361, 1316.
209. Locke, A. E.; Dooley, K. J.; Tinker, S. W., et al. Variation
in Folate Pathway Genes Contributes to Risk of Congenital Heart Defects among Individuals with Down Syndrome.
Genet. Epidemiol. 2010, 34, 613623.
210. Hassold, T.; Hunt, P. To Err (Meiotically) is Human: The
Genesis of Human Aneuploidy. Nat. Rev. Genet. 2001, 2,
280291.
211. Arbuzova, S.; Cuckle, H.; Mueller, R.; Sehmi, I. Familial
Down Syndrome: Evidence Supporting Cytoplasmic Inheritance. Clin. Genet. 2001, 60, 456462.
212. De Souza, E.; Halliday, J.; Chan, A., etal. Recurrence Risks
for Trisomies 13, 18, and 21. Am. J. Med. Genet. A 2009,
149A, 27162722.
213. Korenberg, J. R.; Chen, X. N.; Schipper, R., et al. Down
Syndrome Phenotypes: The Consequences of Chromosomal
Imbalance. Proc. Natl. Acad. Sci. USA 1994, 91, 4997
5001.
214. Shapiro, B. L. Down Syndromea Disruption of Homeostasis. Am. J. Med. Genet. 1983, 14, 241269.
215. FitzPatrick, D. R. Transcriptional Consequences of Autosomal Trisomy: Primary Gene Dosage with Complex Downstream Effects. Trends Genet. 2005, 21, 249253.
216. Antonarakis, S. E.; Lyle, R.; Dermitzakis, E. T., etal. Chromosome 21 and Down Syndrome: From Genomics to Pathophysiology. Nat. Rev. Genet. 2004, 5, 725738.
217. Hattori, M.; Fujiyama, A.; Taylor, T. D., et al. The DNA
Sequence of Human Chromosome 21. Nature 2000, 405,
311319.
218. Rachidi, M.; Lopes, C. Mental Retardation in Down Syndrome: From Gene Dosage Imbalance to Molecular and Cellular Mechanisms. Neurosci. Res. 2007, 59 (4), 349369.
219. Olson, L. E.; Richtsmeier, J. T.; Leszl, J., etal. A Chromosome 21 Critical Region Does Not Cause Specific Down Syndrome Phenotypes. Science 2004, 306, 687690.
220. Lyle, R.; Gehrig, C.; Neergaard-Henrichsen, C., etal. Gene
Expression from the Aneuploid Chromosome in a Trisomy
Mouse Model of Down Syndrome. Genome Res. 2004, 14,
12681274.

25

221. Belichenko, N. P.; Belichenko, P. V.; Kleschevnikov, A. M.,

etal. The Down Syndrome Critical Region is Sufficient in
the Mouse Model to Confer Behavioral, Neurophysiological,
and Synaptic Phenotypes Characteristic of Down Syndrome.
J. Neurosci. 2009, 29 (18), 59385948.
222. Park, J.; Oh, Y.; Chung, K. C., etal. Two Key Genes Closely
Implicated with the Neuropathological Characteristics in
Down Syndrome: DYRK1A and RCAN1. BMB Rep. 2009,
42 (1), 615.
223. Ruparelia, A.; Wiseman, F.; Sheppard, O., etal. Down Syndrome and the Molecular Pathogenesis Resulting from Trisomy of Human Chromosome 21. J. Biomed. Res. 2010, 24,
8799.
224. Rachidi, M.; Lopes, C. Mental Retardation and Associated
Neurological Dysfunctions in Down Syndrome: A Consequence of Dysregulation in Critical Chromosome 21 Genes
and Associated Molecular Pathways. Eur. J. Paediatr. Neurol. 2008, 12, 168182.
225. Ronan, A.; Fagan, K.; Christie, L., et al. Familial 4.3 Mb
Duplication of 21q22 Sheds New Light on the Down Syndrome Critical Region. J. Med. Genet. 2007, 44, 448451.
226. Hook, E. B. Chromosome Abnormalities: Prevalence, Risks
and Recurrence. In Prenatal Diagnosis and Screening; Brock,
D. H. J.; Rodeck, C. H.; Ferguson-Smith, M. A., Eds.; Churchill
Livingstone: Edinburgh, 1992; pp 351392.
227. Warburton, D.; Dallaire, L.; Thangavelu, M., etal. Trisomy
Recurrence: A Reconsideration Based on North American
Data. Am. J. Hum. Genet. 2004, 75, 376385.
228. Kovaleva, N. V. Germ-Line Transmission of Trisomy 21:
Data from 80 Families Suggest an Implication of Grandmaternal Age and a High Frequency of Female-Specific Trisomy
Rescue. Mol. Cytogenet. 2010, 3, 37.
229. Delhanty, J. D. Inherited Aneuploidy: Germline Mosaicism.
Cytogenet. Genome Res. 2011, 133, 136140.
230. Hudson, S. B.; Coddington, C. C.; Walker, D. L., etal. Preimplantation Genetic Screening in a Case of Recurrent Trisomy 21 Offspring. Fertil. Steril. 2009, 930, e17e18.
231. Pradhan, M.; Dalal, A.; Khan, F., etal. Fertility in Men with
Down Syndrome: A Case Report. Fertil. Steril. 2006, 86,
1765e11765e3.
232. Chen, C. P.; Chern, S. R.; Tsai, F., et al. Down Syndrome
due to Unbalanced Homologous Acrocentric Rearrangements and its Recurrence in Subsequent Pregnancies: Prenatal Diagnosis by Amniocentesis. Taiwan J. Obstet. Gynecol.
2009, 48, 403407.
233. Kovaleva, N. V.; Shaffer, L. G. Under-Ascertainment of
Mosaic Carriers of Balanced Homologous Acrocentric
Translocations and Isochromosomes. Am. J. Med. Genet. A
2003, 121A, 180187.
234. Bint, S. M.; Ogilvie, C. M.; Flinter, F. A., et al. Meiotic
Segregation of Robertsonian Translocations Ascertained
in Cleavage-Stage EmbryosImplications for Preimplantation Genetic Diagnosis. Hum. Reprod. 2011, 26, 1575
1584.
235. Dominguez, M. G.; Rivera, H.; Vasquez, A. I., etal. Interchange Trisomy 21 by t(1;21)(p22;q22)mat. Genet. Couns.
2001, 12, 363367.
236. Gair, J. L.; Arbour, L.; Rupps, R., etal. Recurrent Trisomy
21: Four Cases in Three Generations. Clin. Genet. 2005, 68,
430435.
237. Edwards, Jh; Harnden, Dg; Cameron, Ah A New Trisomic
Syndrome. Lancet 1960, 9, 787790.
238. Sepulveda, W.; Wong, A. E.; Dezerga, V. First-Trimester
Sonographic Findings in Trisomy 18: A Review of 53 Cases.
Prenat. Diagn. 2010, 30, 256259.
239. Wapner, R.; Thorn, E.; Simpson, J. L., etal. First-Trimester
Screening for Trisomies 21 and 18. N. Engl. J. Med. 2003,
349, 14051413.

26

CHAPTER 43 Autosomal Trisomies

240. Bronsteen, R.; Lee, W.; Vettraino, I. M., et al. Second-

Trimester Sonography and Trisomy 18. J. Ultrasound. Med.
2004, 23, 233240.
241. Watson, W. J.; Miller, R. C.; Wax, J. R., etal. Sonographic
Findings of Trisomy 18 in the Second Trimester of Pregnancy. J. Ultrasound Med. 2008, 27, 10331038.
242. Ettema, A. M.; Wenghoefer, M.; Hansmann, M., etal. Prenatal Diagnosis of Craniomaxillofacial Malformations: A
Characterization of Phenotypes in Trisomies 13, 18, and
21 by Ultrasound and Pathology. Cleft Palate Craniofac. J.
2010, 47, 189196.
243. Lai, S.; Lau, W. L.; Leung, W. C., etal. Is Ultrasound Alone
Enough for Prenatal Screening of Trisomy 18? A Single Centre Experience in 69 Cases over 10years. Prenat. Diagn.
2010, 30, 10941099.
244. Sibiude, J.; Gavard, L.; Floch-Tudal, C., etal. Perinatal Care
and Outcome of Fetuses with trisomies 13 and 18 Following
a Parental Decision Not to Terminate the Pregnancy. Fetal
Diagn. Ther. 2011, 29, 233237.
245. Merritt, T.A.; Catlin, A.; Peverini, R.; Wool, C. Decisions
Regarding the Treatment and Management of Trisomy 18
and 13 Infants. Neo Rev. 2011, accepted for publication.
246. Carey, J. C. Trisomy 18 and Trisomy 13 Syndromes in
Management of Genetic Syndromes; Wiley Blackwell, 2010,
807823.
247. Wilkinson, D. J. C. Antenatal Diagnosis of Trisomy
18, Harm, and Parental Choice. J. Med. Ethics 2010, 36,
644645.
248. Baty, B. J.; Blackburn, B. L.; Carey, J. C. Natural History
of Trisomy 18 and Trisomy 13: I. Growth, Physical Assessment, Medical Histories, Survival, and Recurrence Risk. Am.
J. Med. Genet. 1994, 49, 175188.
249. Baty, B. J.; Jorde, L. B.; Blackburn, B. L.; Carey, J. C. Natural History of Trisomy 18 and Trisomy 13: II. Psychomotor
Development. Am. J. Med. Genet. 1994, 49, 189194.
250. Rosa, R. F. M.; Rosa, R. C. M.; Lorenzen, M. B., etal. Trisomy 18: Experience of Reference Hospital from the South
of Brazil. Am. J. Med. Genet. A 2011, 155, 15291535.
251. Vendola, C.; Canfield, M.; Dalger, S. P., et al. Survival of
Texas Infants Born with Trisomies 21, 18 and 13. Am.
J. Med. Genet. A 2010, 152A, 360366.
252. Niedrist, D.; Riegel, M.; Achermann, J., etal. Survival with
Trisomy 18-Data from Switzerland. Am. J. Med. Genet. A
2006, 140A, 952959.
253. McCaffrey, F. Around PediHeart: Trisomy 18, an Ethical
Dilemma. Pediatr. Cardiol. 2002, 23, 181.
254. Yates, A. R.; Hoffman, T. M.; Shepherd, E., etal. Pediatric
Sub-Specialist Controversies in the Treatment of Congenital
Heart Disease in Trisomy 13 or 18. J. Genet. Couns. 2011,
20, 495509.
255. Muneuchi, J.; Yamamoto, J.; Takahashi, Y., etal. Outcomes
of Cardiac Surgery in Trisomy 18 Patients. Cardiol. Young
2011, 21, 209215.
256. Tadaki, T.; Kamiyama, R.; Okamura, H. O.; Ohtani, I.
Anomalies of the Auditory Organ in Trisomy 18 Syndrome:
Human Temporal Bone Histopathological Study. J. Laryngol. Otol. 2003, 117, 580583.
257. Kelly, M.; Robinson, B. W.; Moore, J. W. Trisomy 18 in
a 20-Year-Old Woman. Am. J. Med. Genet. 2002, 112,
397399.
258. Ries, M. D.; Ray, S.; Winter, R. B.; Bowen, J. R. Scoliosis in
Trisomy 18. Spine 1990, 15, 12811284.
259. Van Dyke, D. C.; Allen, M. Clinical Management Considerations in Long-Term Survivors with Trisomy 18. Pediatrics
1990, 85, 753759.
260. Anderson, C. E.; Punnett, H. H.; Huff, V.; de Chadarevian,
J. P. Characterization of a Wilms Tumor in a 9-Year-Old Girl
with Trisomy 18. Am. J. Med. Genet. A 2003, 121, 5255.

261. Bove, K. E.; Soukup, S.; Ballard, E. T.; Ryckman, F. Hepatoblastoma in a Child with Trisomy 18: Cytogenetics, Liver
Anomalies, and Literature Review. Pediatr. Pathol. Lab.
Med. 1996, 16, 253262.
262. Armistead, J.; Khatkar, S.; Meyer, B., etal. Mutation of a Gene
Essential for Ribosome Biogenesis, EMG1, Causes BowenConradi Syndrome. Am. J. Hum. Genet. 2009, 84, 728739.
263. Riemersma, S.; Vincent, A.; Beeson, D., et al. Association
of Arthrogryposis Multiplex Congenita with Maternal Antibodies Inhibiting Fetal Acetylcholine Receptor Function.
J. Clin. Invest. 1996, 98, 23582363.
264. Vogt, J.; Harrison, B. J.; Spearman, H., etal. Mutation Analysis of CHRNA1, CHRNB1, CHRND, and RAPSN Genes
in Multiple Pterygium Syndrome/Fetal Akinesia Patients.
Am. J. Hum. Genet. 2008, 82, 222227.
265. Vogt, J.; Morgan, N. V.; Marton, T., etal. Germline Mutation in DOK7 Associated with Fetal Akinesia Deformation
Sequence. J. Med. Genet. 2009, 46, 338340.
266. Slavotinek, A.; Poyser, L.; Wallace, A., et al. Two Unique
Patients with Trisomy 18 Mosaicism and Molecular Marker
Studies. Am. J. Med. Genet. A 2003, 117, 282288.
267. Tucker, M. E.; Garringer, H. J.; Weaver, D. D. Phenotypic
Spectrum of Mosaic Trisomy 18: Two New Patients, a Literature Review, and Counseling Issues. Am. J. Med .Genet.
A 2007, 143, 505517.
268. Bettio, D.; Levi Setti, P.; Bianchi, P., etal. Trisomy 18 Mosaicism in a Woman with Normal Intelligence. Am. J. Med.
Genet. A 2003, 120A, 303304.
269. Kazerouni, N. N.; Currier, R. J.; Flessel, M., etal. Detection
Rate of Quadruple-Marker Screening Determined by Clinical Follow-Up and Registry Data in the Statewide California
Program, July 2007 to February 2009. Prenat. Diagn. 2011,
Epub ahead of print.
270. Chen, C. P.; Chern, S. R.; Tsai, F., etal. A Comparison of
Maternal Age, Sex Ratio and Associated Major Anomalies
among Fetal Trisomy 18 Cases with Different Cell Division
of Error. J. Prenat. Diagn. 2005, 25, 327330.
271. Bugge, M.; Brandt, C. A.; Petersen, M. B. DNA Studies of
Mono- and Pseudodicentric Isochromosomes 18q. Am. J.
Med. Genet. A 2004, 127, 230233.
272. Pal, S.; Siti, M. I.; Ankathil, R.; Zilfalil, B. A. Two Cases of
Isochromosome 18q Syndrome. Singapore Med. J. 2007, 48,
e146e150.
273. Morrissette, J. J.; Medne, L.; Bentley, T., et al. A Patient
with Mosaic Partial Trisomy 18 Resulting from Dicentric
Chromosome Breakage. Am. J. Med. Genet. A 2005, 137,
208212.
274. Hecht, F.; Bryant, J. S.; Gruber, D., etal. The Nonrandomness of Chromosomal Abnormalities: Association of Trisomy 18 and Downs Syndrome. N. Engl. J. Med. 1964, 271,
10811086.
275. Patau, K.; Smith, D. W.; Therman, E., etal. Multiple Congenital Anomaly Caused by an Extra Autosome. Lancet
1960, 1, 790793.
276. Oostra, R. J.; Baljet, B.; Dijkstra, P. F.; Hennekam, R. C.
Congenital Anomalies in the Teratological Collection of
Museum Vrolik in Amsterdam, The Netherlands. I: Syndromes with Multiple Congenital Anomalies. Am. J. Med.
Genet. 1998, 77, 100115.
277. Chen, C. P. Placental Abnormalities and Preeclampsia in Trisomy 13 Pregnancies. Taiwan J. Obstet. Gynecol. 2009, 48,
38.
278. Has, R.; Ibrahimolu, L.; Ergene, H., et al. Partial Molar
Appearance of the Placenta in Trisomy 13. Fetal Diagn.
Ther. 2002, 17, 205208.
279. Sener, R. N. Bilateral, Perisylvian and Rolandic Cortical
Dysplasia in Trisomy 13 Syndrome. J. Neuroradiol. 1996,
23 (4), 231233.

CHAPTER 43 Autosomal Trisomies

280. Gomi, K.; Sato, Y.; Tanaka, M., et al. Specificity of Splenopancreatic Field Abnormality in Trisomy 13 Syndrome:
Macroscopic and Histological Analysis in 21 Autopsy Cases.
Pathol. Int. 2009, 59, 147151.
281. Chen, C. P. Prenatal Sonographic Features of Fetuses in Trisomy 13 Pregnancies (III). Taiwan J. Obste. Gynecol. 2009,
48, 342349.
282. Daniel, A.; Athayde, N.; Ogle, R., etal. Prospective Ranking
of the Sonographic Markers for Aneuploidy: Data of 2143
Prenatal Cytogenetic Diagnoses Referred for Abnormalities
on Ultrasound. Aust. N. Z. J. Obstet. Gynaecol. 2003, 43,
1626.
283. Solomon, B. D.; Rosenbaum, K. N.; Meck, J. M.; Muenke,
M. Holoprosencephaly due to Numeric Chromosome
Abnormalities. Am. J. Med. Genet. C Semin. Med. Genet.
2010, 154C (1), 146148.
284. Wenghoefer, M.; Ettema, A. M.; Sina, F., et al. Prenatal
Ultrasound Diagnosis in 51 Cases of Holoprosencephaly:
Craniofacial Anatomy, Associated Malformations, and
Genetics. Cleft Palate Craniofac. J. 2010, 47 (1), 1521.
285. Kaneko, Y.; Kobayashi, J.; Yamamoto, Y., et al. Intensive
Cardiac Management in Patients with Trisomy 13 or Trisomy 18. Am. J. Med. Genet. 2008, 146A, 13721380.
286. Cordero, D. R.; Bendavid, C.; Shanske, A. L., et al.
Holoprosencephaly-Polydactyly Syndrome: In Search of an
Etiology. Eur. J. Med. Genet. 2008, 51, 106112.
287. Chen, M.; Yeh, G. P.; Shih, J. C.; Wang, B. T. Trisomy 13
Mosaicism: Study of Serial Cytogenetic Changes in a Case
from Early Pregnancy to Infancy. Prenat. Diagn. 2004, 24,
137143.
288. Wallerstein, R.; Yu, M. T.; Neu, R. L., et al. Common
Trisomy Mosaicism Diagnosed in Amniocytes Involving Chromosomes 13, 18, 20 and 21: Karyotype-Phenotype Correlations.
Prenat. Diagn. 2000, 20, 103122.

27

289. Hsu, H. F.; Hou, J. W. Variable Expressivity in Patau Syndrome is Not All Related to Trisomy 13 Mosaicism. Am. J.
Med. Genet. A 2007, 143, 17391748.
290. Happle, R. Phylloid Hypomelanosis is Closely Related to
Mosaic Trisomy 13. Eur. J. Dermatol. 2000, 10, 511512.
291. Jinawath, N.; Zambrano, R.; Wohler, E., etal. Mosaic Trisomy 13: Understanding Origin Using SNP Array. J. Med.
Genet. 2011, 5, 323326.
292. Aypar, E.; Yildirim, M. S.; Sert, A., etal. A Girl with Metopic
Synostosis and Trisomy 13 Mosaicism: Case Report and
Review of the Literature. Am. J. Med. Genet. A 2011, 155A,
638641.
293. Bugge, M.; Collins, A.; Hertz, J. M., et al. Non Disjunction of Chromosome 13. Hum. Molec. Genet. 2007, 16,
204210.
294. Mahjoub, M.; Mehdi, M.; Brahem, S. J., etal. Chromosomal
Segregation in Spermatozoa of Five Robertsonian Translocation
Carriers t(13;14). Assist. Reprod. Genet. 2011, Epub ahead of
print.
295. Irving, M. D.; Buiting, K.; Kanber, D., etal. Segmental Paternal Uniparental Disomy (patUPD) of 14q32 with Abnormal
Methylation Elicits the Characteristic Features of Complete
patUPD14. Am. J. Med. Genet. A 2010, 152A, 19421950.
296. Hoffmann, K.; Heller, R. Uniparental Disomies 7 and 14.
Best Pract. Res. Clin. Endocrinol. Metab. 2011, 25, 77100.
297. Engels, H.; Eggermann, T.; Caliebe, A., etal. Genetic Counseling in Robertsonian Translocations der(13;14): Frequencies of Reproductive Outcomes and Infertility in 101
Pedigrees. Am. J. Med. Genet. A 2008, 146A, 26112616.

Biography
 r Cynthia Curry is a clinical geneticist, Professor of Pediatrics at UCSF San Francisco and
D
adjunct Professor of Pediatrics at Stanford. She practices in Fresno, California, where she
is director of a State of California Prenatal Diagnosis Center and Genetic Medicine Central
California. She is a graduate of Mt Holyoke College and Yale University School of Medicine.
She is trained in pediatrics at the University of Washington and the University of Minnesota.
She completed a fellowship in clinical genetics at UCSF. She has served on the American Board
of Medical Genetics and on the board of the American Society of Human Genetics. Her research
interests include microarray abnormalities, skeletal dysplasias and syndrome delineation.