Overview

A trisomy is a genetic abnormality in which there are three copies,

instead of the normal two, of a particular chromosome. A trisomy is a type of
aneuploidy (an abnormal number of chromosomes). Full trisomy means that an
entire extra chromosome has been copied. Partial trisomy means that there is an
extra copy of part of a chromosome. Trisomies are sometimes characterized as
Autosomal trisomies (trisomies of the non-sex chromosomes) and Sex-
chromosome trisomies. Autosomal trisomies are described by referencing the
specific chromosome that has an extra copy. This condition, however, usually
results in spontaneous miscarriage in the first trimester.

Most organisms that reproduce sexually have pairs of chromosomes in

each cell, with one chromosome inherited from each parent. In such organisms,
a process called meiosis creates cells called gametes (eggs or sperm) that have
only one set of chromosomes. The number of chromosomes is different for
different species. Human beings have 46 chromosomes

The most common types of autosomal trisomy that survive to birth in humans
are:
 Trisomy 21 (Down syndrome)
 Trisomy 18 (Edwards syndrome)
 Trisomy 13 (Patau syndrome)
 Trisomy 12 (Chronic Lymphocytic Leukemia)
 Trisomy 9
 Trisomy 8 (Warkany syndrome 2)
 Trisomy 22

Edwards’s Syndrome Or Trisomy 18 is a genetic disorder caused by the

presence of all or part of an extra 18th chromosome. It is named after John H.
Edwards, who first described the syndrome in 1960. It is the second most
common autosomal trisomy, after Down syndrome that carries to term. Trisomy
18 is caused by the presence of three as opposed to two copies of chromosome
18 in a fetus or infant's cells. The syndrome has a very low rate of survival,
resulting from heart abnormalities, kidney malformations, and other internal
organ disorders.

Patau syndrome or trisomy 13 is a chromosomal abnormality, a syndrome in

which a patient has an additional chromosome 13 due to a nondisjunction of
chromosomes during meiosis. Some are caused by Robertsonian translocations.
The risk of this syndrome in the offspring increases with maternal age at
pregnancy, with about 31 years being the average. Patau syndrome affects
approximately one in 10,000 live births. Most cases of Patau syndrome are not
inherited, but occur as random events during the formation of reproductive cells
(eggs and sperm). An error in cell division called non-disjunction can result in
reproductive cells with an abnormal number of chromosomes. For example, an
egg or sperm cell may gain an extra copy of the chromosome. If one of these
atypical reproductive cells contributes to the genetic makeup of a child, the child
will have an extra chromosome 13 in each of the body's cells.

Chronic lymphoid leukemia (CLL) or trisomy 12 is the most common type of

leukemia. Leukemia’s are cancers of the white blood cells (leukocytes). CLL
affects B cell lymphocytes. B cells originate in the bone marrow, develop in the
lymph nodes, and normally fight infection by producing antibodies. In CLL, the
DNA of a B cell is damaged, so that it cannot produce antibodies. Additionally, B
cells grow out of control and accumulate in the bone marrow and blood, where
they crowd out healthy blood cells. CLL is a stage of small lymphocytic
lymphoma (SLL), a type of B-cell lymphoma, which presents primarily in the
lymph nodes. CLL and SLL are considered the same underlying disease, just
with different appearances. Most people are diagnosed without symptoms as the
result of a routine blood test that returns a high white blood cell count, but, as it
advances, CLL results in swollen lymph nodes, spleen, and liver, and eventually
anemia and infections. Early CLL is not treated, and late CLL is treated with
chemotherapy and monoclonal antibodies. The disease is easily diagnosed. CLL
is usually first suspected by the presence of a lymphocytosis, an increase in one
type of the white blood cell, on a complete blood count (CBC) test. This
frequently is an incidental finding on a routine physician visit. Most often the
lymphocyte count is greater than 4000 cells per microlitre (µl) of blood but can be
much higher. The presence of a lymphocytosis in an elderly individual should
raise strong suspicion for CLL and a confirmatory diagnostic test, in particular
flow cytometry, should be performed unless clinically unnecessary. The
diagnosis of CLL is based on the demonstration of an abnormal population of B
lymphocytes in the blood, bone marrow, or tissues that display an unusual but
characteristic pattern of molecules on the cell surface. This atypical molecular
pattern includes the co-expression of cells surface markers cluster of
differentiation 5 (CD5) and cluster of differentiation 23 (CD23). In addition, all the
CLL cells within one individual are clonal, that is genetically identical. Chronic
lymphocytic leukemia may transform into Richter's syndrome, a term used to
describe the development of fast-growing diffuse large B cell lymphoma,
prolymphocytic leukemia, Hodgkin disease, or acute leukemia in a patient who
has chronic lymphocytic leukemia. Its incidence is estimated to be around 5%.

Trisomy 9 is a chromosomal disorder caused by having three copies (trisomy) of

chromosome number 9. It can appear with or without mosaicism. Trisomy 9 is a
chromosomal disorder caused by having three copies (trisomy) of chromosome
number 9. It can appear with or without mosaicism. Symptoms vary, but usually
result in dysmorphisms in the skull, nervous system, and mental retardation.
Dysmorphisms in the heart, kidneys, and musculoskeletal system may also
occur. An infant with complete trisomy 9 surviving 20 days after birth showed
clinical features including a small face, wide fontanel, prominent occiput,
micrognathia, low set ears, up slanting palpebral fissures, high arched palate,
short sternum, overlapping fingers, limited hip abduction, rocker bottom feet,
heart murmurs and also a webbed neck.

Warkany syndrome 2, or trisomy 8, is an aberration of human chromosome 8

that results in trisomy of the chromosome. This causes severe effects on the
developing fetus. Trisomy is also found in some cases of chronic myeloid
leukaemia, potentially as a result of karyotypic instability caused by the bcr:abl
fusion gene. Complete trisomy 8 frequently results in miscarriage, while those
with "trisomy 8 mosaicism" are more likely to survive. Common findings include
retarded psychomotor development, moderate to severe mental retardation,
variable growth patterns which can result in either abnormally short or tall stature,
an expressionless face, and many musculoskeletal, visceral, and eye
abnormalities, as well as other anomalies. The type and severity of symptoms
are dependent upon the location and proportion of trisomy 8 cells compared to
normal cells. Complete trisomy 8 is often an early lethal condition, whereas
mosaic individuals with a low proportion of affected cells may exhibit a
comparatively mild range of physical abnormalities and developmental delay.

Trisomy 22 is a chromosomal disorder in which there are three copies of

chromosome 22 rather than two. It is a frequent cause of spontaneous abortion
during the first trimester of pregnancy. Progression to the second trimester and
livebirth are rare.

Down syndrome, or trisomy 21, is a chromosomal condition caused by the

presence of all or part of an extra 21st chromosome. It is named after John
Langdon Down, the British physician who described the syndrome in 1866. The
condition was identified as a chromosome 21 trisomy by Jérôme Lejeune in
1959. The condition is characterized by a combination of major and minor
differences in structure. Down syndrome in a fetus can be identified with
amniocentesis during pregnancy or in a baby at birth. Often Down syndrome is
associated with some impairment of cognitive ability and physical growth, and a
particular set of facial characteristics. Individuals with Down syndrome tend to
have a lower-than-average cognitive ability, the average IQ of children with Down
syndrome is around 50, compared to normal children with an IQ of 100. A small
number have a severe to high degree of intellectual disability. Many of the
common physical features of Down syndrome may also appear in people with a
standard set of chromosomes, including microgenia (an abnormally small chin),
an unusually round face, macroglossia (protruding or oversized tongue), an
almond shape to the eyes caused by an epicanthic fold of the eyelid, up slanting
palpebral fissures (the separation between the upper and lower eyelids), shorter
limbs, a single transverse palmar crease (a single instead of a double crease
across one or both palms), poor muscle tone, and a larger than normal space
between the big and second toes. Health concerns for individuals with Down
syndrome include a higher risk for congenital heart defects, gastroesophageal
reflux disease, recurrent ear infections, obstructive sleep apnea, and thyroid
dysfunctions.
LABORATORY OF TRISOMY 21
Screen When Detection False Description
performed rate positive
rate
Quad screen 15–20 81% 5% This test measures the
maternal serum alpha
feto protein (a fetal liver
protein), estriol (a
pregnancy hormone),
human chorionic
gonadotropin (hCG, a
pregnancy hormone),
and inhibit-Alpha
(INHA).
Nuchal 10–13.5 85% 5% Uses ultrasound to
translucency/fre measure Nuchal
e beta/PAPPA Translucency in
screen (aka "1st addition to the freeBeta
Trimester hCG and PAPPA
Combined Test") (pregnancy-associated
plasma protein A). NIH
has confirmed that this
first trimester test is
more accurate than
second trimester
screening methods.
Performing an NT
ultrasound requires
considerable skill; a
Combined test may be
less accurate if there is
operator error, resulting
in a lower-than-
advertised sensitivity
and higher false-
positive rate, possibly
in the 5-10% range.
Integrated Test 10-13.5 95% 5% The Integrated test
and 15–20 uses measurements
from both the 1st
Trimester Combined
test and the 2nd
trimester Quad test to
yield a more accurate
 screening result.
Because all of these
tests are dependent on
accurate calculation of
the gestational age of
the fetus, the real-world
false-positive rate is
>5% and maybe be
closer to 7.5%.

EXAMS AND TESTS

A doctor can often make an initial diagnosis of Down syndrome at birth

based on how the baby looks. The doctor may hear a heart murmur when
listening to the baby's chest with a stethoscope.

A blood test can be done to check for the extra chromosome and confirm the
diagnosis. See: Chromosome studies

Other tests that may be done include:

 Echocardiogram to check for heart defects (usually done soon after birth)
 ECG
 X-rays of the chest and gastrointestinal tract

Persons with Down syndrome need to be closely screened for certain medical
conditions. They should have:

 Eye exam every year during infancy

 Hearing tests every 6 - 12 months, depending on age
 Dental exams every 6 months
 X-rays of the upper or cervical spine between ages 3 - 5 years
 Pap smears and pelvic exams beginning during puberty or by age 21

SIGNS AND SYMPTOMS

Down syndrome can result from several different genetic mechanisms.

This results in a wide variability in individual signs and symptoms due to complex
gene and environment interactions. Prior to birth, it is not possible to predict the
symptoms that an individual with Down syndrome will develop.
Individuals with Down syndrome may have some or all of the following physical
characteristics:
 microgenia (abnormally small chin),
 oblique eye fissures with epicanthic skin folds on the inner corner of the
eyes (formerly known as a mongoloid fold),
  muscle hypotonia (poor muscle tone),
 a single palmar fold,
 a protruding tongue (due to small oral cavity, and an enlarged tongue
near the tonsils) or macroglossia,
 a short neck,
 white spots on the iris known as Brushfield spots,
 excessive joint laxity including atlanto-axial instability,
 excessive space between large toe and second toe,
 a single flexion furrow of the fifth finger,
 Higher number of ulnar loop dermatoglyphs,
 may have a broad head and a very round face
 Decreased muscle tone at birth
 Excess skin at the nape of the neck
 Flattened nose
 Single crease in the palm of the hand
 Small ears
 Small mouth
 Upward slanting eyes
 Wide, short hands with short fingers

Most individuals with Down syndrome have intellectual disability in the mild
(IQ 50–70) to moderate (IQ 35–50) range, with individuals having Mosaic Down
syndrome typically 10–30 points higher.
Language skills show a difference between understanding speech and
expressing speech, and commonly individuals with Down syndrome have a
speech delay Fine motor skills are delayed and often lag behind gross motor
skills and can interfere with cognitive development. Effects of the condition on the
development of gross motor skills are quite variable. Some children will begin
walking at around 2 years of age, while others will not walk until age 4. Physical
therapy, and/or participation in a program of adapted physical education (APE),
may promote enhanced development of gross motor skills in Down syndrome
children. Growth parameters such as height, weight, and head circumference
are smaller in children with DS than with typical individuals of the same age.
Adults with DS tend to have short stature — the average height for men is 5 feet
1 inch (157 cm) and for women is four feet 9 inches (144 cm). Individuals with DS
are also at increased risk for obesity as they age.

COMPLICATIONS

Individuals with Down syndrome have a higher risk for many conditions. The
medical consequences of the extra genetic material in Down syndrome are highly
variable and may affect the function of any organ system or bodily process.
Some problems are present at birth, such as certain heart malformations.
  Congenital heart disease
The incidence of congenital heart disease in children with Down syndrome is up
to 50%. An atrioventricular septal defect also known as endocardial cushion
defect is the most common form with up to 40% of patients affected.

 Malignancies
Hematologic malignancies such as leukemia are more common in children with
DS. In particular, the risk for acute lymphoblastic leukemia is at least 10 times
more common in DS and for the megakaryoblastic form of acute myelogenous
leukemia is at least 50 times more common in DS. Transient leukemia is a form
of leukemia which is rare in individuals without DS but affects up to 20 percent of
newborns with DS. This form of leukemia is typically benign and resolves on its
own over several months, though it can lead to other serious illnesses
 Thyroid disorders
Individuals with DS are at increased risk for dysfunction of the thyroid gland, an
organ which helps control metabolism. Low thyroid (hypothyroidism) is most
common, occurring in almost a third of those with DS. This can be due to
absence of the thyroid at birth (congenital hypothyroidism) or due to attack on the
thyroid by the immune system.

 Gastrointestinal
Down syndrome increases the risk of Hirschsprung's disease, in which the nerve
cells that control the function of parts of the colon are not present. This results in
severe constipation. Other congenital anomalies occur more frequently in DS
include duodenal atresia, annular pancreas, and imperforate anus.

 Infertility
There is infertility amongst both males and females with Down syndrome; males
are usually unable to father children, while females demonstrate significantly
lower rates of conception relative to unaffected individuals Women with DS are
less fertile and often have difficulties with miscarriage, premature birth, and
difficult labor. Without pre-implantation genetic diagnosis, approximately half of
the offspring of someone with Down syndrome also have the syndrome
themselves. Men with DS are almost uniformly infertile, exhibiting defects in
spermatogenesis.

Treatment
There is no specific treatment for Down syndrome. A child born with a
gastrointestinal blockage may need major surgery immediately after birth. Certain
heart defects may also require surgery. When breast-feeding, the baby should be
well supported and fully awake. The baby may have some leakage because of
poor tongue control. However, many infants with Down syndrome can
successfully breast-feed.
Obesity can become a problem for older children and adults. Getting
plenty of activity and avoiding high-calorie foods are important. Before beginning
sports activities, the child's neck and hips should be examined. Behavioral
training can help people with Down syndrome and their families deal with the
frustration, anger, and compulsive behavior that often occur. Parents and
caregivers should learn to help a person with Down syndrome deal with
frustration. At the same time, it is important to encourage independence.
Adolescent females and women with Down syndrome are usually able to get
pregnant. There is an increased risk of sexual abuse and other types of abuse in
both males and females. It is important for those with Down syndrome to:
 Be taught about pregnancy and taking the proper precautions
 Learn to advocate for themselves in difficult situations
 Be in a safe environment

If the person has any heart defects or problems, check with the physician
about the need for antibiotics to prevent heart infections called endocarditis.
Special education and training is offered in most communities for children with
delays in mental development. Speech therapy may help improve language
skills. Physical therapy may teach movement skills. Occupational therapy may
help with feeding and performing tasks. Mental health care can help both parents
and the child manage mood or behavior problems. Special educators are also
often needed.

RECOMMENDATION

I recommend genetic counseling for persons with a family history of Down

syndrome who wish to have a baby. A woman's risk of having a child with Down
syndrome increases as she gets older. The risk is significantly higher among
women age 35 and older. Couples who already have a baby with Down
syndrome have an increased risk of having another baby with the condition.
Tests such as nuchal translucency ultrasound, amniocentesis, or chorionic villus
sampling can be done on a fetus during the first few months of pregnancy to
check for Down syndrome.

PATHOPHYSIOLOGY

The extra chromosome 21 affects almost every organ system and results
in a wide spectrum of phenotypic consequences. These include life-threatening
complications, clinically significant alteration of life course (eg, mental
retardation), and dysmorphic physical features. Down syndrome decreases
prenatal viability and increases prenatal and postnatal morbidity. Affected
children have delays in physical growth, maturation, bone development, and
dental eruption. The extra copy of the proximal part of 21q22.3 appears to result
in the typical physical phenotype: mental retardation, characteristic facial
features, hand anomalies, and congenital heart defects. Molecular analysis
reveals that the 21q22.1-q22.3 region, or Down syndrome critical region (DSCR),
appears to contain the gene or genes responsible for the congenital heart
disease observed in Down syndrome. A new gene, DSCR1, identified in region
21q22.1-q22.2, is highly expressed in the brain and the heart and is a candidate
for involvement in the pathogenesis of Down syndrome, particularly, in the
mental retardation and/or cardiac defects.