Congenital Cytogenetic Abnormalities

Congenital cytogenetic abnormalities - UpToDate 11/05/19 3(09
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Congenital cytogenetic abnormalities

Author: Stanislawa Weremowicz, PhD
Section Editors: Charles J Lockwood, MD, MHCM, Louise Wilkins-Haug, MD, PhD, Helen V Firth, DM, FRCP, DCH
Deputy Editor: Elizabeth TePas, MD, MS
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2019. | This topic last updated: Feb 01, 2018.
INTRODUCTION
Chromosomal aberrations are due to a change in the normal chromosome number or a change in the
structure of a chromosome. They may involve one, two, or more chromosomes and may involve only part of
a chromosome or the whole chromosome. Congenital anomalies, growth deficiency, and intellectual disability
are findings often present in individuals with chromosome abnormalities, although some cytogenetic
aberrations have little to no clinical effect. Rapid progress in human cytogenetics has demonstrated a causal
relationship between various chromosomal abnormalities and their phenotypic manifestations. In addition,
the specific chromosomal etiologies of a wide variety of syndromes have been established. (See
"Chromosomal translocations, deletions, and inversions" and "Overview of genetic variation" and "Genomic
disorders: An overview".)
This topic reviews the most common chromosomal abnormalities and discusses when to refer a
patient/parent for a genetic evaluation. Diseases caused by point mutations and other small genetic defects
are discussed elsewhere. (See "Microdeletion syndromes (chromosomes 1 to 11)" and "Microdeletion
syndromes (chromosomes 12 to 22)" and "Microduplication syndromes" and "Sex chromosome
abnormalities" and "Down syndrome: Clinical features and diagnosis".)
INCIDENCE
Fifteen percent of clinically recognized pregnancies result in fetal death [1]. Cytogenetic abnormalities are
more common in spontaneous abortions (50 percent of fetal deaths <20 weeks) than in stillbirths (6 to 13
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percent of fetal deaths ≥20 weeks). A 1998 multicenter survey of 103,069 live births in the United States
identified major chromosomal abnormalities in 1 in 140 live births (table 1) [2]. However, the incidence of
chromosomal abnormalities is dependent upon the sample and population studied and the type of diagnostic
testing used. As an example, the incidence is lower among live births than among abortuses, second
trimester fetuses, or stillbirths. Trisomy 21 (Down syndrome) remains the most common chromosomal
abnormality among liveborn infants [3-5].
Diagnosis of chromosomal abnormalities by conventional karyotyping has several limitations compared with
a subsequently developed technique based upon microarray analysis [1,6,7]. As an example, analysis of
macerated fetuses and nonviable tissues from spontaneous abortions and stillbirths has low yield. In
addition, chromosome banding techniques can only detect major structural abnormalities. Array comparative
genomic hybridization (aCGH) can detect smaller copy number variations (eg, DNA gains and losses) and
has a higher yield when performed on fetal tissue from pregnancy losses. Thus, aCGH may become the
preferred type of testing to analyze fetal loss as it becomes more readily available, less costly, and easier to
perform. The use of aCGH in prenatal diagnosis of chromosomal abnormalities and postnatal evaluation of
pregnancy loss is discussed in detail separately. (See "Use of chromosomal microarray in obstetrics" and
"Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Detecting cytogenetic
abnormalities' and "Genomic disorders: An overview".)
Total versus live birth prevalence — Estimates of total and live-birth prevalence of trisomy 21 (Down
syndrome) and other trisomies vary depending upon demographics, race, year of data collection, regional
differences in prenatal screening and pregnancy termination, and maternal age. A comparison of
amniocentesis and liveborn data regarding the incidence of trisomy 21 (Down syndrome) is shown in the
table (table 2). The maternal age-specific rate of trisomy 21, as well as other chromosomal abnormalities, is
approximately 30 percent higher when diagnosed in the early second trimester by amniocenteses than when
diagnosed after birth. These differences can be explained, in part, by an increased late spontaneous fetal
loss rate (after the early second trimester) for fetuses with chromosomal abnormalities [8,9].
A European study of 21 population-based registries for the epidemiologic surveillance of congenital

anomalies (EUROCAT) that included 6.1 million births from 1990 to 2009 revealed an increase in total
prevalence of trisomy 21 over time to 22 in 10,000 (1 in 455) [10]. This change was attributed to an increase
in the proportion of births in population to mothers aged 35 years and older from 13 percent in 1990 to 19
percent in 2009. At the same time, the live-birth prevalence of trisomies 13, 18, and 21 remained stable
overall (1 in 20,830 for trisomy 13, 1 in 9614 for trisomy 18, and 1 in 890 for trisomy 21). The stable live-birth
prevalence compared with the rise in total prevalence is most likely due to increased prenatal screening and
pregnancy termination [10], as well as an increase in fetal loss rate in trisomy pregnancies with advancing
maternal age [11].
There is no national registry for Down syndrome or other birth defects in the United States. Thus, the exact
number of trisomy 21 live births in the United States is unknown. Data from the United States Centers for
Disease Control and Prevention indicated an increase of trisomy 21 live births by 24 percent, from 1 in 1053
during the period from 1979 to 1983 to 1 in 847 from the years 1999 to 2003. In comparison, a decrease in
trisomy 21 live births, from 1 in 900 in 1989 to 1 in 1070 in 2006, was seen in data based upon birth
certificates from the National Center for Health Statistics (NCHS) [12]. The highest prevalence reported was
from the 1998 multicenter United States survey, with a rate of 1 in 730 live births [2].
Data from spontaneous abortuses — Approximately one-half of spontaneous abortions have an abnormal
chromosomal complement (on Giemsa [G]-banded karyotyping), which is the probable etiology of the
pregnancy loss. Autosomal trisomies are strongly correlated with maternal age and account, in part, for the
higher rate of spontaneous abortion in women over 40 years [13,14]. (See "Effects of advanced maternal age
on pregnancy".)
A review of 8841 spontaneous abortions found that 41 percent had chromosomal abnormalities visible on G-
banded karyotyping [2]. The most frequent types of abnormalities detected were:
● Autosomal trisomies – 52 percent

● Polyploidies – 22 percent
● Monosomy X – 19 percent
● Other – 7 percent
Trisomy 16, with an incidence of approximately 1.5 percent in clinically recognized pregnancies, is the most
common trisomy among abortuses and is never encountered in live births [15,16]. The cause of trisomy 16 in
almost all zygotes is nondisjunction in maternal meiosis I [17]. Embryos with full trisomy 16 are
spontaneously aborted or have arrested development between 8 to 15 weeks' gestational age. Some survive
beyond this gestational age and are diagnosed prenatally by chorionic villus sampling (CVS) or
amniocentesis. These surviving embryos are virtually always mosaic as a result of trisomy rescue, a process
in which one of the trisomic chromosomes is lost during mitotic cell division [18].
Data from stillbirths and neonatal deaths — Stillbirth in the United States is defined as a fetal loss at a
gestational age greater than 20 weeks, whereas neonatal death refers to death occurring within the first four
weeks after a live birth.
In one series, karyotyping of a combined group of 823 stillbirths and neonatal deaths found a major
chromosomal abnormality in 6.3 percent [2]. The frequency of abnormal karyotype in macerated stillbirths
(deaths occurring during pregnancy), nonmacerated or fresh stillbirths (deaths occurring during labor or
delivery), and neonatal deaths was approximately 12, 4, and 6 percent, respectively. The abnormalities
reported were mostly comprised of trisomies 18, 13, and 21; sex chromosome aneuploidy; and unbalanced
translocations. The frequency of chromosomal abnormality in this combined group was approximately 10-fold
higher than the incidence of 0.7 percent observed in live births. In another series of 750 intrauterine fetal
deaths, chromosomal abnormalities visible on G-banded karyotyping were identified in 38 and 5 percent of
fetuses with and without morphologic abnormalities, respectively [19].
In fresh stillbirths with chromosomal abnormalities, sex chromosome abnormalities were observed in 20
percent, autosomal trisomies in 70 percent, and balanced structural rearrangements in 10 percent. In
neonatal deaths, the type and frequency of chromosomal abnormalities were broader: monosomy X (7
percent), other sex chromosomal abnormalities (10 percent), autosomal trisomies (55 percent), triploidy (3
percent), balanced structural rearrangement (7 percent), unbalanced structural rearrangement (16 percent),
and other unspecified chromosome abnormality (3 percent) [20].
Fetuses with congenital anomalies — The prevalence of chromosomal abnormalities visible by G-banded
karyotyping in fetuses with congenital anomalies ranges from 2 to 35 percent, with the highest rate in fetuses
with multiple anomalies as opposed to an isolated anomaly [21]. The risk of chromosomal abnormality also
varies according to the type of isolated anomaly. As an example, duodenal atresia is associated with a
relatively high rate of abnormal karyotype (eg, approximately 30 percent of liveborn infants with duodenal
atresia are diagnosed with trisomy 21 [Down syndrome]), whereas an isolated urinary tract anomaly carries a
low rate of chromosomal abnormality.
WHEN TO REFER FOR GENETIC EVALUATION
A cytogenetic abnormality may be identified during prenatal screening, or it may be suspected prenatally
based upon ultrasound findings or postnatally due to congenital anomalies, growth failure, intellectual
disability with or without dysmorphic features, developmental delay, and/or autism. Studies used to detect
cytogenetic abnormalities are discussed in detail separately. (See "Tools for genetics and genomics:
Cytogenetics and molecular genetics", section on 'Detecting cytogenetic abnormalities'.)
All cases of stillbirth and neonatal death should be investigated to provide adequate counseling for parents
regarding the cause of death and risk of recurrence in future pregnancy. The cytogenetic evaluation is an
important component of perinatal necroscopy and is discussed in detail separately [22]. (See "Fetal death
and stillbirth: Incidence, etiology, and prevention" and "Evaluation of stillbirth" and "Use of chromosomal
microarray in obstetrics", section on 'Fetal demise'.)
Indications for prenatal genetic counseling and general and specific prenatal screening are discussed in
detail separately. (See "Prenatal care: Initial assessment" and "Sonographic findings associated with fetal
aneuploidy" and "Chorionic villus sampling" and "Diagnostic amniocentesis", section on 'Prenatal diagnosis'
and "Down syndrome: Overview of prenatal screening".)
Indications for postnatal genetic counseling and testing in general for certain specific disorders are also
discussed separately. (See "Genetic testing" and "Birth defects: Approach to evaluation", section on
'Laboratory studies' and "Down syndrome: Clinical features and diagnosis" and "Autism spectrum disorder:
Evaluation and diagnosis", section on 'Genetic testing' and "Intellectual disability in children: Evaluation for a
cause", section on 'Chromosomal abnormalities'.)
NUMERIC ABNORMALITIES
Individuals with numerical chromosome abnormalities (aneuploidies) may have multiple congenital
malformations that can involve one or more organ systems. Intellectual disability and small stature are the
two most constant features; low birth weight, dysmorphic features, and failure to thrive are other frequently
observed problems. The presence of mosaicism can lead to variability in the phenotype, as well as the
survival. Trisomies are the most common aneuploidies seen. Autosomal aneuploidies are reviewed here.
Sex chromosome aneuploidies are reviewed separately. (See "Sex chromosome abnormalities", section on
'Numeric abnormalities (aneuploidies)'.)
Trisomy 21 (Down syndrome) — Trisomy 21 (MIM #190685) is the most common chromosome abnormality
among live births (1 in 730 live births) and the most frequent form of intellectual disability caused by a
microscopically demonstrable chromosomal aberration [23-26].
The three main types of cytogenetic abnormalities that result in the Down syndrome phenotype and their
relative proportions are:
● Trisomy 21 (47,+21) – Approximately 95 percent.
● Robertsonian translocation involving chromosome 21 (figure 1) – 3 to 4 percent. (See "Chromosomal

translocations, deletions, and inversions", section on 'Robertsonian translocations'.)
● Trisomy 21 mosaicism (47,+21/46) – 1 to 2 percent. Two populations of cell types, one with the normal
46 chromosomes and the other with 47,+21, are present.
Most individuals with Down syndrome have free trisomy 21 (47,+21) [23]. Meiotic nondisjunction error is the
cause in 95 percent of cases, and the error occurs at mitosis in somatic cells in the remaining 5 percent of
cases [27]. In approximately 90 percent of cases, the extra chromosome 21 originates from the mother. This
explains, in part, why the risk of this type of Down syndrome increases with advancing maternal age (table
2). The recurrence rate is approximately 1 percent in younger women; the maternal age-related risk is used if
it is greater than 1 percent [28]. Studies of infants with trisomy 21 identified paternal trisomy in 7 percent of
cases [29,30]. A slightly higher rate (approximately 11 percent) of a paternally derived extra copy of
chromosome 21 is seen in cases of trisomy 21 diagnosed prenatally [31].
In Down syndrome patients with an unbalanced Robertsonian translocation, the entire long arm of one
chromosome 21 is translocated to the long arm of an acrocentric chromosome (ie, chromosome 13, 14, 15,
21, or 22) [23]. The most common form of this translocation involves chromosomes 14 and 21 [46,der(14;21)
(q10;q10),+21]. These individuals have 46 chromosomes, but one chromosome 14 contains the long arms of
both chromosomes 14 and 21. Therefore, they actually have three copies of the long arm of chromosome 21
(two normal chromosome 21s and a third long arm translocated to chromosome 14), which results in Down
syndrome. Trisomy 21 resulting from a Robertsonian translocation is not related to maternal age.
A parental carrier of a balanced Robertsonian translocation involving chromosome 21, eg, 45,der(14;21)
(q10;q10), has an observed risk as high as 15 percent of having an offspring born with an unbalanced
translocation resulting in Down syndrome (figure 1). The risk is highest if the mother, rather than the father, is
the translocation carrier (10 to 15 versus 2 to 5 percent). However, the majority of translocations resulting in
Down syndrome occur de novo, with only 3 to 4 percent having a familial etiology. (See "Chromosomal
translocations, deletions, and inversions".)
Duplication of the long (q) arm of chromosome 21 [dup(21q)] represents a rare form of Down syndrome with
an estimated incidence of approximately 1 in 45,000 live births. Approximately 95 percent of dup(21q) are de
novo mutations. DNA polymorphism studies indicate that the majority of the de novo dup(21q) chromosomes
are isochromosomes [i(21q)]. However, Robertsonian translocations [t(21q;21q)] have also been detected
[32]. Interstitial duplication of the critical region 21q22.13-q22.2, resulting in "partial trisomy 21," is another
uncommon cause of Down syndrome [33].
Prenatal screening and diagnosis of Down syndrome and the clinical manifestations and management of the
disorder are discussed in detail separately. (See "Down syndrome: Overview of prenatal screening" and
"Down syndrome: Clinical features and diagnosis" and "Down syndrome: Management".)
Trisomy 18 syndrome — The three main types of trisomy 18 (also called Edwards syndrome [34]) are:
● Trisomy 18 (47,+18) – 90 percent of cases of trisomy 18 are the result of meiotic nondisjunction.
● Translocation involving chromosome 18.
● Trisomy 18 mosaicism (47,+18/46).
Trisomy 18 is the second most common autosomal trisomy observed in live births (1 in 5500 live births)
[23,35]. As with trisomy 21, there is a relationship between advanced maternal age and the occurrence of
trisomy 18 in offspring due to meiotic nondisjunction. There is a 3:1 female to male ratio among affected
infants.
The clinical spectrum of trisomy 18 may involve any organ system [23,36-38]. The major phenotypic features
include intrauterine growth restriction (IUGR), hypertonia, prominent occiput, small mouth, micrognathia,
pointy ears, short sternum, horseshoe kidney, and flexed fingers, with the index finger overlapping the third
finger and the fifth finger overlapping the fourth. Congenital heart disease occurs in greater than 50 percent
of affected individuals with common valvular involvement. Ventricular septal defects and patent duct
arteriosus are the most common defects. The gastrointestinal system is involved in approximately 75 percent
of cases. Meckel's diverticulum and malrotation are the predominant abnormalities. Omphalocele is relatively
common prenatally.
The prenatal sonographic findings of trisomy 18 correspond to the physical abnormalities. IUGR associated
with polyhydramnios, especially in a fetus with abnormal hand positioning ("clenched hands"), is suggestive
of this disorder. Choroid plexus cysts are common. (See "Sonographic findings associated with fetal
aneuploidy".)
The majority of prenatally diagnosed cases of trisomy 18 die in utero [28,39]. In a series of 23 pregnancies
with diagnosed fetal trisomy 18, 14 fetuses died in utero, and the remainder died within 48 hours of birth [40].
In general, 50 percent of affected infants die within the first two weeks of life, and only 5 to 10 percent survive
the first year [23,38,41,42]. However, survival into the school-age years is possible [43]. Severe intellectual
disability is apparent in survivors over one year of age.
A "noninterventional paradigm" of withdrawal of intensive treatment has been recommended for trisomy 18
because of the lethality of the disorder, the severe intellectual disability in those that survive beyond one year
of age, and the lack of a cure, although acceptance of this paradigm is not universal [35,43].
Despite this recommendation, retroactive assessment of hospitalization data on 10,939 patients collected
from the nationally representative United States Kids Inpatient Databases for the years 1997, 2000, 2003,
2006, and 2009 demonstrated that children with trisomy 13 and trisomy 18 received significant inpatient
medical care (eg, over 2500 major therapeutic procedures) [43]. Longer-term survivors made up a sizable
proportion of this group, with over one-third older than one year of age and approximately 10 percent over
eight years of age. In a Canadian cohort study of 254 children with trisomy 18, mean 1-year survival was
12.6 percent, and 10-year survival was 9.8 percent [44]. Most deaths occurred in the first six months of life.
Twenty-three of the 35 children who underwent surgeries ranging from simple interventions such as
myringotomy to complex cardiac repairs survived for at least one year after the first surgery. Data on
intensive treatment of 24 Japanese patients with trisomy 18 that included corrective surgery for
gastrointestinal malformations but not surgery for congenital heart defects showed a survival rate of 25
percent at one year of age (median survival time 152.5 days). These studies suggesting a role for alternative
approaches to care [35].
Treatment and medical intervention depend upon the presence and type of major or life-threatening
abnormalities in the patient. Therapeutic interventions may include gastrointestinal tract, cardiac, orthopedic,
and pharynx/facial/sinus procedures, as well as tracheostomy. A multidisciplinary team including obstetrics,
genetic counseling, pediatricians, surgeons, and social workers are important in providing information on
availability of post-hospitalization care, educational programs, and support organizations.
Trisomy 13 syndrome — Trisomy 13 syndrome is a severe chromosomal disorder caused by an extra copy
of chromosome 13. The three etiologies of trisomy 13 (also called Patau syndrome [45,46]) are:
● Trisomy 13 (47,+13), with three copies of chromosome 13 in each cell of the body as a result of meiotic
error. This form is associated with advanced maternal age.
● Unbalanced Robertsonian translocation, with two normal copies of chromosome 13 and an extra copy of
the long arm of chromosome 13 translocated to one of the acrocentric chromosomes (ie, 14, 14, 21, 22)
resulting in full trisomy 13. This type of trisomy 13 is not related to advanced maternal age. Although a
balanced Robertsonian translocation involving chromosome 13 and 14 (ie, 45,t(13;14)(q10;q10)) is
relatively common, there is a low risk for the carrier to bear offspring with an unbalanced chromosome
complement because the high rate (98 to 99 percent) of early embryonic death [2,47].
● Trisomy 13 mosaicism (47,+13/46), with three copies of chromosome 13 in some cells and two copies in
others. This form is caused by a mitotic nondisjunction error and is not related to maternal age.
Trisomy 13 syndrome is characterized by severe, multiple congenital anomalies. The classic triad is
micro/anophthalmia, cleft lip and/or palate, and postaxial polydactyly, but the clinical presentation in patients
with trisomy 13 can be quite variable [45,48].
Abnormalities observed in ≥50 percent of trisomy 13 patients [49] include:
● Central nervous system (CNS) – Holoprosencephaly with incomplete development of forebrain and
olfactory and optic nerves, severe intellectual disability, deafness
● Craniofacial – Abnormal auricles, microphthalmia/anophthalmia, colobomata, sloping forehead (fissure

or cleft of the iris, ciliary body, or choroid)
● Skin and limbs – Capillary hemangiomata, simian crease, hyperconvex narrow fingernails, polydactyly of
hands and sometimes feet, prominent heel
● Cardiac – Found in approximately 80 percent of patients; includes ventricular septal defect (VSD), patent
ductus arteriosus (PDA), atrial septal defect (ASD), and dextroposition
● Genitalia – Cryptorchidism in males; bicornuate uterus in females
Other abnormalities observed in less than 50 percent of patients include [48,49]:
● Growth – Prenatal growth deficiency
● CNS – Hyper- or hypotonia, agenesis of corpus callosum, cerebral hypoplasia
● Eyes – Hypo- or hypertelorism, cyclopia, upslanting palpebral fissures
● Nose, mouth, mandible – Absent philtrum, narrow palate, micrognathia
● Hands and feet – Retroflexible thumb, syndactyly, cleft between first and second toes, hypoplastic
toenails, radial aplasia
● Abdomen – Omphalocele, incomplete rotation of colon, Meckel diverticulum
● Renal – Polycystic kidney, hydronephrosis, horseshoe kidney
Prenatal sonographic findings of the characteristic CNS defects are the most common fetal signs suggestive
of this diagnosis. (See "Sonographic findings associated with fetal aneuploidy" and "Prenatal diagnosis of
CNS anomalies other than neural tube defects and ventriculomegaly".)
The prevalence of trisomy 13 in newborns is 1 in 5000 [49,50]. The majority of prenatally diagnosed cases of
trisomy 13 die in utero [28,39]. The median survival for liveborn children is seven days, and 91 percent die
within the first year, with the majority (approximately 80 percent) dying within the first month of life
[23,39,47,49]. There are several published cases of patients with trisomy 13 who are over five years of age
[51]. Cardiac anomalies were reported in only 46 percent of the long-lived survivors, in contrast to the much
higher frequency (up to 80 percent) reported in all trisomy 13 cases. This finding suggests that the lower
frequency of heart defects may contribute to the longer survival [51]. Intensive treatments, including
resuscitation and surgical procedures, may prolong survival. As an example, a retrospective study from 1989
to 2010 that included 16 Japanese patients with trisomy 13 who had received intensive treatment showed a
median survival time of 24 months [52]. Severe intellectual disability, seizures, and failure to thrive are
common in survivors over one year of age [23,47,53].
As with trisomy 18, a "noninterventional paradigm" of providing supportive, but not intensive, treatment has
been recommended for trisomy 13 because of the high mortality of the disorder, the severe intellectual
disability in those that survive beyond one year of age, and the lack of a cure [35,43]. However, acceptance
of this paradigm is not universal, because survival beyond infancy is possible, particularly in those who
receive intensive treatment. In a Canadian cohort of 174 children with trisomy 13, mean 1-year survival was
19.8 percent and 10-year survival was 12.9 percent [44]. Most deaths occurred in the first three months of
life. Twenty-nine of the 41 children who underwent surgeries ranging from simple interventions such as
myringotomy to complex cardiac repairs survived for at least one year after the first surgery. Options for
management of trisomy 13 are similar to that for trisomy 18. (See 'Trisomy 18 syndrome' above.)
Trisomy 8 syndrome — Full trisomy 8 is estimated to occur in 0.1 percent of all clinically recognized
pregnancies and is usually lethal [54]. Trisomy 8 is almost always a mosaic form (47,+8/46) in liveborn
infants. The estimated frequency of mosaic trisomy 8 in liveborn infants is 1 in 25,000 to 1 in 50,000 [55]. A
skewed sex ratio (3:1 male:female) is observed in mosaic cases [56,57].
Ultrasonographic detection of agenesis of the corpus callosum and ventriculomegaly should alert to the
possibility of mosaic trisomy 8 [58]. In addition, mosaic trisomy 8 is sometimes associated with an elevated
maternal serum alpha-fetoprotein. A diagnosis of mosaic trisomy 8 can be difficult to establish and can be
missed at amniocentesis [59]. A normal chromosome constitution in lymphocyte culture does not exclude
trisomy 8 mosaicism, since abnormal cell lines are far more likely to be detected in fibroblast cultures (eg,
skin biopsy, or other tissues) than in lymphocytes [60], making the condition difficult to diagnose.
Trisomy 8 mosaicism is also difficult to diagnose postnatally due to great phenotypic variation
[23,54,55,61,62]. The severity of the phenotype does not appear to correlate with the level (ie, percentage)
and distribution of the trisomic cells in tissue types [63]. Characteristic phenotypic features include agenesis
of corpus callosum, ventriculomegaly, skeletal and joint abnormalities, congenital heart defects, deep palmar
and plantar creases, facial dysmorphism, and moderate to severe intellectual disability. The growth of
children with trisomy 8 is variable, ranging from small to tall stature. Life expectancy is usually normal [54].
Molecular studies revealed that trisomy 8 mosaicism in liveborns almost always originates from postzygotic
mitotic error [56,64]. Parental ages of liveborn infants with trisomy 8 mosaicism are usually not increased
[65], and cases with uniparental disomy (UPD) 8 are rare because they can only originate from a meiotic
nondisjunction error.
Genetic counseling is difficult due to great phenotypic variability. Prognosis, management, and treatment
depend upon the specific clinical abnormalities in the patient (eg, repair of cleft palate or heart defects,
surgical intervention for hydronephrosis). Patients and families should be made aware of a possible
association with malignancy [66]. Early assessment for intellectual disability is recommended for additional
assistance in providing special education programs.
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Trisomy 9 syndrome — Full trisomy 9 occurs in approximately 0.1 percent of conceptions and is almost
always lethal [67]. The phenotype appears to be similar in the several liveborn infants described so far and
consists of severe growth restriction, characteristic facial appearance (eg, micrognathia, bulbous nose, low-
set ears), cleft palate, skeletal abnormalities (eg, dislocated joins), heart abnormalities (eg, ventricular septal
defect), hypoplastic genitalia, and renal and brain abnormalities. The survival time after birth varies between
minutes to nine months [68-70].
The majority of liveborn individuals with trisomy 9 have a mosaic karyotype (47,+9/46) that may be detected
in amniocytes or a peripheral blood sample [60,61,68,69]. The constellation of phenotypic abnormalities of
trisomy 9 mosaicism is similar to that seen in liveborn infants with full trisomy 9 described above
[23,60,61,68,69,71]. Failure to thrive, severe intellectual and motor deficiency, cryptorchidism in males, and
renal cysts are common. Death typically occurs at <1 year of age, although longer survival intervals have
been reported [69,72,73].
Based upon molecular studies, it appears that trisomy 9 is caused by a meiotic error, and subsequent trisomy
rescue leads to mosaicism in surviving embryos. In some cases, UPD has been documented in the diploid
cell line [74]. Association with advanced maternal age is observed, similar to other trisomy syndromes [69].
(See "Genetics: Glossary of terms".)
The percentage of mosaicism appears not to correlate with clinical manifestations and does not help to
predict survival. Medical intervention depends upon the presence and severity of abnormalities. Genetic
counseling and early assessment are recommended to provide any necessary special medical/educational
assistance.
Other rare autosomal trisomies — Other autosomal trisomies are rare and have been described largely in
case reports. Most of these individuals have a mosaic karyotype. Mosaic trisomy 14 (47,+14/46) is
associated with growth and intellectual disability, congenital heart defects (especially tetralogy of Fallot and
septal defects), and body and/or facial asymmetry [60,75-78]. Trisomy 22 can occur as a mosaic or full
trisomy [79-85]. The major clinical features are intrauterine growth restriction, microcephaly, abnormal ears,
ear tags, webbed neck/redundant skin, congenital heart defects, renal abnormalities, and long fingers.
Nonmosaic trisomy 22 usually ends in miscarriage; survival beyond the early neonatal period is rare but has
been reported.
The risk level of having documented malformations associated with a given trisomic mosaicism, based upon
cases diagnosed prenatally through amniocentesis and assessed at birth or at pregnancy termination, is as
follows [60]:
● Trisomic mosaicism of chromosome 2, 16, or 22 – Greater than 60 percent
● Trisomic mosaicism of chromosome 5, 9, 14, or 15 – 40 to 59 percent

● Trisomy 12 mosaicism – 26 percent
● Trisomy 7 mosaicism – Up to 19 percent
● Trisomy 17 mosaicism – Low
The prognoses of the remaining rare trisomies have not been determined due to insufficient data [60].
Triploidy syndrome — Triploidy occurs in 1 to 3 percent of clinically recognized pregnancies and accounts
for approximately 20 percent of spontaneous abortions [86]. The frequency in liveborn infants is estimated at
1 in 10,000 [87]. Triploid fetuses that survive to the third trimester usually have severe IUGR [23].
Triploidy refers to a complete extra set of haploid chromosomes derived from the mother (digynic) or the
father (diandric). Digynic triploidy can result from fertilization of a diploid ovum due to an error at either the
first or second meiotic division. Diandric triploidy may occur through fertilization of a normal ovum by a diploid
sperm or by two sperm (dispermy/double fertilization) and is more common than digynic triploidy (90 versus
10 percent) [23].
Two distinct phenotypes have been noted due to an imprinting effect that depends upon the origin of the
extra haploid set [88,89] (see "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)",
section on 'Parent-of-origin effects (imprinting)'). When the triploid is diandric, the placenta is enlarged, and
the histology is consistent with a partial hydatidiform mole (see "Gestational trophoblastic disease:
Pathology"). The fetus is mildly growth restricted, with either head size proportionate to the trunk size or mild
microcephaly. By comparison, a digynic triploid is associated with severe fetal growth restriction, relative
macrocephaly, and a small, noncystic placenta. The digynic triploid fetus tends to survive longer than the
diandric triploid, although there is 100 percent mortality (usually intrauterine, rarely within a few months of
birth). Fetuses with diploid or triploid mosaicism may be viable.
Supernumerary marker chromosome — The term supernumerary marker chromosome (SMC) refers to
any extra, small, structurally altered chromosome in addition to the normal diploid cell line. SMCs were often
uncharacterized by conventional cytogenetic methods due to insufficient banding pattern. Modern molecular
technologies, such as fluorescence in situ hybridization (FISH) and array comparative genomic hybridization
(aCGH), have allowed determination of marker chromosomes deriving from all 46 chromosomes.
The overall incidence of SMC is similar at amniocentesis and in newborns, 0.6 to 1.5 and 0.72 per 1000,
respectively [90-93]. A study performed on 143,000 consecutive prenatal samples, including 44,786 chorionic
villi samples (CVS) and 98,214 amniotic fluid (AF) samples, revealed an overall frequency of 0.073 percent
for a de novo SMC. The overall frequency differed between CVS (ie, 0.103 percent) and AF (ie, 0.059
percent) samples [94]. The difference between karyotype in placental versus fetal tissue most likely reflects a
confined placental mosaicism (CPM).
For the de novo markers, the overall risk for abnormal phenotype has been estimated between 14 and 30
percent. However, the risk for abnormal phenotype is lower (ie, 7 percent) when the marker is derived from
an acrocentric chromosome (13, 14, 21, 22), except for chromosome 15. There is an approximate 28 percent
overall risk for abnormalities in carriers of SMC derived from nonacrocentric chromosomes. However, the risk
may decrease to 18 percent in cases with no congenital abnormalities detected by high-level ultrasound [95].
Thus, identification of the origin and genetic makeup of a marker is crucial for risk calculation and genetic
counseling.
Various cytogenetic and molecular methods can be applied to identify markers, including karyotyping, FISH,
and aCGH. Applying genome-wide microarray is an efficient method to identify and characterize markers, as
well as to detect any additional potential abnormality/imbalance in the genome [96]. There are technical
limitations for each method; for example, neocentromeric markers cannot be identified by FISH with
centromeric alpha satellite DNA probes, and aCGH does not detect minute markers that do not contain
euchromatin or cases with a low level of mosaicism (<10 percent).
The four most common SMCs are discussed below. The terms "pter" and "qter" refer to the terminal parts of
the short and long arms of a chromosome, respectively.
47,+inv dup(15) — This SMC is formed by inverted duplication of the proximal part of chromosome 15. It
is the most common marker found at prenatal testing. The inv dup(15) markers are classified as two
subtypes based upon breakpoint on the long (q) arm: a small inv dup(15) with the break at 15q11 and a large
inv dup(15) containing the Prader-Willi/Angelman critical region (PWACR), with the break at 15q12 or q13.
The small inv dup (15)(q11) can be inherited or de novo. In two large studies, the inv dup(15) accounted for
57 and 25 percent of all markers detected in 39,105 and 100,000 prenatal diagnoses, respectively [92,93].
The majority of carriers have a normal phenotype [97], with some exceptions [98]. There are rare cases of
Angelman or Prader-Willi syndrome due to UPD 15 [99]. Postnatal studies have demonstrated a correlation
among the large inv dup(15)(q12 or q13), (PW/ACR+) marker, and distinctive clinical findings that include
intellectual disability, developmental delay, early central hypotonia, seizures, and autistic behavior [90,99-
102].
In the majority of cases, the inv dup(15)(q12 or q13) is derived from maternal chromosomes at meiosis, is
associated with advanced maternal age at conception, and is almost always de novo [101,103]. Thus, it is
essential to determine whether the 47,+inv dup(15) marker chromosome contains the Prader-Willi/Angelman
syndrome (PW/AS)-critical region when the SMC is prenatally identified as a de novo inv dup(15). The inv
dup(15) markers can be detected by standard chromosome analysis and FISH with probes specific to
centromere of chromosome 15 and to the PW/AS locus or by aCGH to detect and to determine the extent of
the duplication. Methylation study and/or microsatellite analysis should also be performed to determine the
origin of chromosome 15 in the proband. (See "Epidemiology and genetics of Prader-Willi syndrome" and
"Clinical features, diagnosis, and treatment of Prader-Willi syndrome" and "Microdeletion syndromes
(chromosomes 12 to 22)", section on '15q11-13 maternal deletion syndrome (Angelman syndrome)' and
"Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 paternal deletion syndrome
(Prader-Willi syndrome)'.)
47,+i(18p) — This supernumerary marker chromosome is an isochromosome consisting of two identical

copies of the entire short (p) arm of chromosome 18, i(18p). It is one of the most commonly observed
isochromosomes [104]. In the majority of cases, nondisjunction of chromosome 18 occurs in maternal
meiosis II, followed by centromeric misdivision [105]. Mosaic cases (ie, 47,+i(18p)/46) are rare.
Isochromosome 18p is associated with a distinctive syndrome that results from tetrasomy 18p. The most
common clinical features include growth retardation, neonatal hypotonia and feeding problems,
microcephaly, facial dysmorphism [106], cardiac abnormalities (eg, patent ductus arteriosus, ventricular
septal defect, atrial septal defect), cryptorchidism, talipes equinovarus (clubfoot), congenital hip dysplasia,
and mild to moderate intellectual disability and developmental delay [107].
Most cases of tetrasomy 18p are sporadic, although familial cases have been reported [108,109]. Parental
chromosome analysis is recommended for a recurrent risk evaluation.
Evaluations for patients with tetrasomy 18p depend upon the clinical features present and may include
evaluations by ophthalmology, otolaryngology and audiology, cardiology, orthopedics, neurology,
endocrinology, and gastroenterology. Patients may also benefit from referral for developmental services and
specific medical treatment for congenital anomalies.
47,+i(12p) — This supernumerary marker is an isochromosome consisting of two copies of the short (p)
arm of chromosome 12. Mosaicism with a normal cell line frequently occurs [110,111].
Isochromosome 12p results in tetrasomy 12p, also called Pallister-Killian syndrome (MIM #601803). The
exact prevalence of Pallister-Killian syndrome is unknown. It may be underdiagnosed because of broad
phenotype variability. The major clinical manifestations are severe intellectual disability, seizures, hypotonia
with subsequent contractures, coarse and dysmorphic facies, large and abnormal ears, short neck, and
sparse hair [23,112,113].
Chromosome analysis (ie, karyotype, FISH, aCGH) is recommended in suspected cases of Pallister-Killian
syndrome. Cells with 47,+i(12p) are tissue specific in mosaic cases and are more likely to be detected in skin
fibroblasts than in peripheral blood lymphocyte cultures [90]. Thus, different types of tissue (eg, skin biopsy
and/or buccal smears) should be submitted for testing.
Early evaluation assessment for abnormalities requiring surgical intervention is recommended. Some
patients will require multiple corrective surgeries. Enrollment in special education programs should be
considered for patients with milder developmental delay.
47,+inv dup(22)(q11) — This supernumerary bisatellited marker is derived from an inverted duplication of
the short arm (p) and proximal long arm (q) of chromosome 22 (ie, inv dup 22pter—22q11.2), resulting in
tetrasomy of this region of chromosome 22. This defect is associated with cat-eye syndrome, a
developmental disorder characterized by a highly variable phenotype [114,115]. Cat-eye syndrome can be
the result of trisomy or tetrasomy 22q. The name is derived from the vertical iris coloboma. Characteristic
clinical features include preauricular tags and/or pits, iris coloboma, congenital heart disease (total
anomalous pulmonary venous return [TAPVR] is the characteristic defect associated with this condition), anal
anomalies, renal malformation, skeletal abnormalities, and intellectual disability. The clinical manifestation
may vary from very mild to a full pattern and lethal outcome [116-118]. Chromosome analysis of parents is
recommended in children in whom the inv dup(22)(q11) chromosome is detected by cytogenetic analysis due
to the significant phenotypic variation of the disease.
Patients with cat-eye syndrome should be assessed at birth for presence of heart, biliary, and anorectal
abnormalities. Early intervention and treatment can prevent possible future complications, including patient
death.
STRUCTURAL DEFECTS
Structural chromosomal defects include deletions, duplications, translocations, and inversions.

Cytogenetically detectable autosomal deletions are present in 1 in 7000 live births [119]. The incidence of
autosomal duplications is unknown. The more common autosomal deletion and duplication syndromes that
are primarily caused by macrodeletions or duplications (deletions or duplications detectable on chromosomal
banding with light microscopy) are discussed below. Syndromes that are typically caused by submicroscopic
deletions or duplications (microdeletions or microduplications) are reviewed in detail elsewhere. Structural
defects of the sex chromosomes are also covered elsewhere. The mechanisms for structural chromosomal
defects are discussed separately. (See "Microdeletion syndromes (chromosomes 1 to 11)" and
"Microdeletion syndromes (chromosomes 12 to 22)" and "Microduplication syndromes" and "Sex
chromosome abnormalities" and "Genomic disorders: An overview" and "Chromosomal translocations,
deletions, and inversions".)
5p deletion syndrome (cri-du-chat syndrome) — Cri-du-chat (cat cry) (MIM #123450) is a deletion
syndrome, with an incidence of approximately 1 in 45,000 liveborn infants [120,121]. Approximately 85
percent of cases result from a de novo partial deletion of the short arm of chromosome 5 (the deleted
chromosome is of paternal origin in 80 percent) [23]. The remaining cases derive from a parental
translocation involving 5p. The critical region for the high-pitched, cat-like crying is 5p15.3, while the
remaining clinical features of this syndrome are mapped to a smaller region within 5p15.2 (figure 2) [122-
124].
Patients with cri-du-chat or cat cry syndrome have a mew-like cry early on in life that quickly resolves
(apparently related to vocal cord abnormalities) and low birth weight, failure to thrive, hypotonia, psychomotor
delay, intellectual disability, microcephaly, hypertelorism, round face, downslanting palpebral fissures, broad
nasal bridge, and low-set and/or malformed ears [23,121,125,126]. Genotype-phenotype correlation in one
series of 62 patients with terminal deletions showed progressive severity of clinical features (eg, degree of
microcephaly) and psychomotor retardation according to the size of the deletion [126]. With advancing age,
the clinical manifestations become less striking, making diagnosis more difficult [127]. Most children, but not
all, have low weight for age and, to a lesser extent, shortened height for age [128].
18q deletion syndrome — 18q- syndrome (MIM #601808) is a contiguous gene deletion syndrome with a
frequency of approximately 1 in 40,000 live births [129]. The structural abnormalities of 18q- include proximal
interstitial deletions, complex cryptic rearrangements, and distal deletions causing de Grouchy syndrome
[130]. Most cases are sporadic, although familial cases have been reported [131]. (See "Genomic disorders:
An overview", section on 'Contiguous gene syndromes'.)
The breakpoints and size of deletions vary between patients, as do the phenotypic features [132]. The most
frequent clinical features include growth delay (some with growth hormone deficiency), intellectual disability,
autoimmune disorders, selective immunoglobulin A (IgA) deficiency, microcephaly, midface hypoplasia, flat
philtrum, carp-shaped mouth, broad nasal bridge, hearing impairment, eye anomalies, tapered fingers,
excess whorls on the fingertips, and neurologic and genitourinary abnormalities [23,132-138].
Several studies have evaluated patients at the clinical, cytogenetic, and molecular (eg, array comparative
genomic hybridization [aCGH]) levels for genotype/phenotype correlations [138,139]. One aCGH study
performed on 29 carriers detected six interstitial deletions and 23 terminal deletions of variable size and
differing breakpoint locations. Microcephaly was consistently present in patients with interstitial deletions and
terminal deletions that mapped to a 1Mb critical region at 18q21.33. Short stature was diagnosed in 15
patients with overlapping deletions in several regions. An earlier study mapped a 2Mb critical region for
growth hormone insufficiency to 18q23 [140]. Among genes mapped to this region were myelin basic protein
(MBP) and galanin receptor (GALR1), which plays a role in growth hormone response and is therefore a
good candidate gene for growth hormone insufficiency. White matter alteration and delayed myelination
overlap with this region [141]; therefore, MBP is a prime candidate gene in delayed myelination [142].
Intellectual disability was mapped proximal to 18q21.33. Deletions distal to this region were not consistently
associated with intellectual impairment, which was very mild if present.
Chromosome analysis (ie, Giemsa [G]-banded karyotype, fluorescence in situ hybridization [FISH], aCGH) is
recommended in suspected cases of 18q deletion. Chromosome analysis of parents is recommended for
recurrent risk evaluation. Prognosis, management, and treatment depend upon the specific clinical
abnormalities. Some patients benefit from growth hormone treatment [143], as well as physical, occupational,
and speech therapy. Early intervention is beneficial, and genetic counseling is recommended.
SUMMARY
● A major chromosomal abnormality is found in approximately 1 in 140 live births. Trisomy 21 (Down
syndrome) is the most common congenital cytogenetic abnormality. (See 'Incidence' above.)
● Individuals with unbalanced autosomal aberrations may have congenital abnormalities that can involve
one or more organ systems. Intellectual disability and small stature are the two most constant features.
Low birth weight and failure to thrive are other frequently observed problems. Trisomies are the most
common aneuploidies seen. (See 'Numeric abnormalities' above.)
● Autosomal trisomies, with the exception of trisomy 21 (Down syndrome), are almost always lethal.
Mosaicism alters survivorship for some autosomal trisomies. Survival can be prolonged by application of
intensive medical intervention. (See 'Numeric abnormalities' above.)
● The term "supernumerary marker chromosome" (SMC) refers to any extra, small, structurally altered
chromosome in addition to the normal diploid cell line. Identification and characterization of marker
chromosomes have diagnostic and prognostic value and may provide information for a more accurate
estimation of recurrence risk. (See 'Supernumerary marker chromosome' above.)
● Structural chromosomal defects include deletions, duplications, translocations, and inversions. Cri-du-
chat (cat cry) syndrome is one of the most common human deletion syndromes. (See 'Structural defects'
above.)
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Topic 452 Version 26.0
GRAPHICS
Chromosomal abnormalities among livebirths
Total livebirths 103,069
Male livebirths 61,484
Female livebirths 41,585
Type of abnormality Number of cases Rate

Autosomal trisomies
47, +21 141 1/730
47, +18 19 1/5424
47, +13 6 1/17,178
Sex chromosome abnormalities - males
47, XXY 73 1/842
47, XYY 66 1/931
Sex chromosome abnormalities - females
47, XXX 45 1/924
45, X 15 1/2772
Structural abnormalities
Balanced 139 1/490
Unbalanced 43 1/1516
Total abnormalities 736 1/140
Data from: Hsu LYF. Prenatal diagnosis of chromosomal abnormalities through amniocentesis. In: Genetic Disorders and the Fetus,
4th ed, Milunsky A (Ed), Johns Hopkins University Press, Baltimore 1998. p.180.
Graphic 52347 Version 4.0
Maternal age-related risk for common fetal trisomies across pregnancy
Combined
Down Edwards Patau
Maternal trisomy
syndrome/trisomy syndrome/trisomy syndrome/trisomy
age 21/18/13 risk
21 risk (1:n) 18 risk (1:n) 13 risk (1:n)
(years) (1:n)
CVS Amnio Term CVS Amnio Term CVS Amnio Term CVS Amnio Term
18 1150 1210 1495 2520 3150 9010 6985 7945 13,700 710 790 1175
19 1145 1205 1490 2515 3145 8985 6970 7930 13,670 705 785 1165
20 1135 1200 1475 2510 3135 8960 6955 7905 13,635 705 780 1160
21 1125 1185 1460 2500 3125 8930 6925 7875 13,580 695 775 1150
22 1110 1165 1440 2490 3110 8885 6890 7835 13,510 690 765 1135
23 1090 1150 1415 2470 3090 8825 6840 7780 13,410 680 755 1115
24 1065 1120 1380 2450 3060 8745 6770 7700 13,275 670 740 1095
25 1030 1085 1340 2415 3020 8630 6675 7590 13,090 650 720 1065
26 975 1030 1285 2375 2970 8480 6545 7445 12,840 625 690 1025
27 925 975 1220 2320 2900 8280 6375 7250 12,500 600 660 980
28 855 900 1140 2245 2805 8010 6145 6990 12,050 560 620 920
29 770 825 1045 2145 2680 7660 5850 6655 11,470 515 575 850
30 685 730 935 2020 2525 7215 5475 6225 10,735 465 520 770
31 590 630 815 1865 2330 6655 5015 5700 9830 410 455 675
32 490 535 695 1675 2095 5990 4475 5085 8770 350 390 580
33 400 430 570 1460 1825 5220 3870 4400 7585 290 325 480
34 310 345 455 1225 1535 4380 3235 3680 6345 230 260 385
35 240 260 350 990 1235 3530 2615 2975 5130 180 200 300
36 180 195 265 765 955 2725 2055 2335 4030 135 150 225
37 130 145 195 565 710 2025 1580 1800 3100 99 115 170
38 95 105 145 410 510 1455 1210 1375 2370 72 83 125
39 71 79 110 290 360 1035 930 1060 1825 53 61 94
40 52 60 85 205 255 735 730 830 1430 39 45 72
41 40 46 66 150 185 530 590 670 1160 30 35 56
42 32 38 54 110 140 395 495 560 970 23 28 45
43 27 31 45 87 110 310 425 485 840 19 23 37
44 22 26 39 70 88 250 380 435 745 16 19 32
45 19 23 34 60 74 215 350 395 685 14 16 28
46 18 21 31 52 65 185 325 370 640 12 15 25
47 16 19 29 47 59 170 310 355 610 11 14 24
48 15 18 27 44 55 155 300 340 590 11 13 22
49 15 18 26 41 52 150 290 330 570 10 12 21
The table shows the expected prevalence of three common autosomal trisomies (21, 18, and 13) individually (first three
boxed columns) and together (last boxed column). Within each of these groups, the prevalence is shown at three different
times in gestation. These include at the time of CVS at approximately 11 to 13 weeks of gestation, amniocentesis at
approximately 15 to 18 weeks of gestation, and at term. Each row of the table shows these results for a given maternal
age (eg, the row "35 years" includes women age 35.0 through 35.9, average 35.5 years) at the expected date of delivery.
For example, consider a 32.4-year-old woman being counseled prior to a CVS procedure who has no specific indications of
an abnormality other than age (eg, no abnormal ultrasound findings or pregnancy history of aneuploidy). The chance that
the CVS will identify a fetus with Down syndrome is 1:490, with trisomy 18 is 1:1675, and with trisomy 13 is 1:4475.
Together, these pose a current combined risk of 1:350. However, her chance of having a term birth with Down syndrome
(1:696), trisomy 18 (1:5990), or trisomy 13 (1:8770) is lower. Together, these pose a term risk of 1:580.
CVS: chorionic villus sampling; amnio: amniocentesis.
References:
1. Morris JK, Savva GM. The risk of fetal loss following a prenatal diagnosis of trisomy 13 or trisomy 18. Am J Med Genet 2008;
146A:827.
2. Morris JK, Mutton DE, Alberman E. Revised estimates of the maternal age specific live birth prevalence of Down's syndrome. J
Med Screen 2002; 9:2.
3. Savva GM, Morris JK, Mutton DE, Alberman E. Maternal age-specific fetal loss rates in Down syndrome pregnancies. Prenat
Diagn 2006; 26:499.
4. Savva GM, Walker K, Morris JK. The maternal age-specific live birth prevalence of trisomies 13 and 18 compared to trisomy 21
(Down syndrome). Prenat Diagn 2010; 30:57.
Robertsonian translocation
Example of a Robertsonian translocation in which the long arms of one

chromosome 14 and one chromosome 21 are fused in the carrier parent (upper
panel) is a cause of Down syndrome in the offspring. One of the three viable
gametes will be normal, one will have a balanced rearrangement, and one will
contain the fused chromosome [der(14;21)] as well as the unaffected
chromosome 21. Normal fertilization of this gamete results in a fetus with trisomy
21. Other possible segregation products are gametes lacking a chromosome 21,
gametes lacking a chromosome 14, and gametes with one chromosome 14 and a
derivative chromosome der(14;21), all of which are not viable.
Courtesy of Iris Schrijver, MD.
Cri du chat syndrome
The cri du chat syndrome is due to a large deletion of the terminal short arm
of chromosome 5. The size of the deletion may be different in each patient,
but it always encompasses chromosomal bands 5p15.2 and 5p15.3.
The representation of chromosome 5 (on the left) indicates the deletion
breakpoint that was identified in one patient. The shortened p-arm of a
chromosome 5, stained by GTG (G-banding with trypsin and Giemsa)-
banding, is shown on the right. For comparison, a chromosome 5 from a
normal individual is placed in the middle. The boxed fragment indicates the
extent of the deletion in the affected chromosome.
Courtesy of Athena Cherry, Stanford Hospital and Clinics.
Contributor Disclosures
Stanislawa Weremowicz, PhD Nothing to disclose Charles J Lockwood, MD, MHCM Nothing to disclose Louise
Wilkins-Haug, MD, PhD Nothing to disclose Helen V Firth, DM, FRCP, DCH Nothing to disclose Elizabeth TePas, MD,
MS Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by
vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

Congenital Cytogenetic Abnormalities - UpToDate

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Congenital cytogenetic abnormalities - UpToDate 11/05/19 3(09

Official reprint from UpToDate®

A European study of 21 population-based registries for the epidemiologic surveillance of congenital

● Autosomal trisomies – 52 percent

WHEN TO REFER FOR GENETIC EVALUATION

● Trisomy 21 (47,+21) – Approximately 95 percent.

● Robertsonian translocation involving chromosome 21 (figure 1) – 3 to 4 percent. (See "Chromosomal

Abnormalities observed in ≥50 percent of trisomy 13 patients [49] include:

● Craniofacial – Abnormal auricles, microphthalmia/anophthalmia, colobomata, sloping forehead (fissure

● Genitalia – Cryptorchidism in males; bicornuate uterus in females

Other abnormalities observed in less than 50 percent of patients include [48,49]:

● Growth – Prenatal growth deficiency

● CNS – Hyper- or hypotonia, agenesis of corpus callosum, cerebral hypoplasia

● Eyes – Hypo- or hypertelorism, cyclopia, upslanting palpebral fissures

● Nose, mouth, mandible – Absent philtrum, narrow palate, micrognathia

● Abdomen – Omphalocele, incomplete rotation of colon, Meckel diverticulum

● Renal – Polycystic kidney, hydronephrosis, horseshoe kidney

● Trisomic mosaicism of chromosome 2, 16, or 22 – Greater than 60 percent

● Trisomic mosaicism of chromosome 5, 9, 14, or 15 – 40 to 59 percent

confined placental mosaicism (CPM).

47,+i(18p) — This supernumerary marker chromosome is an isochromosome consisting of two identical

Structural chromosomal defects include deletions, duplications, translocations, and inversions.

Use of UpToDate is subject to the Subscription and License Agreement.

16. Wolstenholme J. An audit of trisomy 16 in man. Prenat Diagn 1995; 15:109.

66. Danesino C, Pasquali F, Dellavecchia C, et al. Constitutional trisomy 8 mosaicism: mechanism of

18p. Am J Med Genet A 2006; 140:276.

deletions. Am J Hum Genet 1997; 60:860.

Topic 452 Version 26.0

Chromosomal abnormalities among livebirths

Total livebirths 103,069

Male livebirths 61,484

Female livebirths 41,585

Type of abnormality Number of cases Rate

47, +21 141 1/730

47, +18 19 1/5424

47, +13 6 1/17,178

Sex chromosome abnormalities - males

47, XXY 73 1/842

47, XYY 66 1/931

Sex chromosome abnormalities - females

47, XXX 45 1/924

Balanced 139 1/490

Total abnormalities 736 1/140

Graphic 52347 Version 4.0

Maternal age-related risk for common fetal trisomies across pregnancy

38 95 105 145 410 510 1455 1210 1375 2370 72 83 125

39 71 79 110 290 360 1035 930 1060 1825 53 61 94

40 52 60 85 205 255 735 730 830 1430 39 45 72

41 40 46 66 150 185 530 590 670 1160 30 35 56

42 32 38 54 110 140 395 495 560 970 23 28 45

43 27 31 45 87 110 310 425 485 840 19 23 37

44 22 26 39 70 88 250 380 435 745 16 19 32

45 19 23 34 60 74 215 350 395 685 14 16 28

46 18 21 31 52 65 185 325 370 640 12 15 25

47 16 19 29 47 59 170 310 355 610 11 14 24

48 15 18 27 44 55 155 300 340 590 11 13 22

49 15 18 26 41 52 150 290 330 570 10 12 21

CVS: chorionic villus sampling; amnio: amniocentesis.

Graphic 75423 Version 11.0

Example of a Robertsonian translocation in which the long arms of one

Courtesy of Iris Schrijver, MD.

Graphic 81746 Version 1.0