Down Syndrome
Down Syndrome
 Is a genetic disorder caused by extra genetic material
(DNA) (ie, presence of an extra 21st chromosome)
 Common autosomal aneuplody (trisomy 21).
 It is the common of the chromosomal disorders and
leading cause of mental retardation.
 Incidence : 1 in 700 births and the incidence increases
with the advancing age of the mother usually above 35
yrs .
Cont…
 Human cells normally have 46 chromosomes that can be
arranged in 23 pairs. One set of 23 chromosomes comes
from the mother (ovum) and the other half of the 23 pairs
comes from the father (sperm cell).
Trisomy 21
 In Down syndrome, 95% of all cases are caused by either
the sperm or the egg cell having two 21st chromosomes
instead of one, so the resulting fertilized egg has three
21st chromosomes. Hence the scientific name, trisomy 21.
 Recent research has shown that in these cases,
approximately 90% of the time the abnormal cells are the
ovum.
 The cause of the extra chromosome isn't known, but there
is definitely connection with the mother's age.
Robertsonian translocation
 Occurs in 3-4% of cases.
 In this case, the genetic material is rearranged so that
some of the 13th, 14th, or 15th chromosome is replaced
by an extra copy of genetic material from the 21st
chromosome.
 The overall number of chromosomes remains normal
(46 chromosomes in 23 pairs), but there are 3 copies of
the 21st chromosome material.
 Partial trisomy 21
Sometimes the extra genetic material only comes from
part of the long arm of the 21st chromosome (21q), and
this is called partial trisomy 21
Mosaicism and trisomy 21
 In these cases, people have a mixture of cells . Some
cells have a normal set of chromosomes, and other
cells have trisomy 21.
 In cellular mosaicism, the mixture is seen in
different cells of the same type.
 In tissue mosaicism, one set of cells, such as all blood
cells, may have normal chromosomes, and another
type, such as all skin cells, may have trisomy 21.
Genes that may have input into Down syndrome include:
 SOD1 (superoxide dismutase 1 gene) overexpression may cause premature aging and
decreased function of the immune system.
COL6A1 (alpha-1 collagen VI gene) overexpression may be the cause of heart defects.
ETS2 (ETS2 oncogene) overexpression may be the cause of skeletal abnormalities.
CAF1A (chromatin assembly factor 1, p60 subunit) overexpression may cause
problems with DNA synthesis.
CBS (cystathione beta synthase) overexpression may disrupt metabolism and DNA
repair.
DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase
1A) overexpression may be the cause of mental retardation.
CRYA1 (alpha-1 crystallin) overexpression may be the cause of cataracts.
GART (glycinamide ribonucleotide synthetase) overexpression may disrupt DNA
synthesis and repair.
IFNAR (interferon alpha receptor) overexpression may interfere with the immune
system as well as other organ systems.
 Remember that no gene has yet been fully linked to any feature associated with
Down syndrome.
Clinical features
A. General
 Mental retardation, hypotonia (poor Moro’s reflex
and hyper flexibility of the joint ), reduce life
expectancy by 40%.
B. Face and skull:
 Oblique palpebral fissure, marked epicanthal fold,
flat nasal bridge , low set ears, and flat occiput,
protruding tongue .
C. Thorax and abdomen:

congenital heart malformation (ventricular septal
defect), duodenal atresia ,imperforated anus,
umbilical hernia.
D. Hand and feets:

short and broad hands ,single palmar (simian)
crease, wide gap between 1st and 2nd toes (sandal
gap) ,clinodactyl (hypoplasia of the middle phalanx
with a single flexion crease of the 5th finger.
Characteristic flat facies with
hypertelorism, depressed
nasal bridge, protrusion of
the tongue, a single palmar
simian crease
Small auricle and anomalies of the folds
wide gap between the first and
second toes
 protuberant abdomen and
an umbilical hernia
Investigation
1.


Karyotyping
Trisomy 21 (about 95%): 47XX +21 or 47,XY=21
Translocation 21/14, 21/22
Treatment
Advice to the parents .
2. Genetic counselling .
i. Antenatal diagnosis is possible by aminocentesis (1516 wks) and choronic villi sampling (9-11 wks)
ii. Detection of carrier is possible by chromosome
analysis, DNA analysis technique
(thalassaemia,haemophilia)
1.
Supportive management of the
morbid condition such as:
 Recurrent chest infection
 Appropriate management of the congenital anomalies
such as imperforated anus ,VSD
Down Syndrome Life Expectancy Statistics:
 Down Syndrome life expectancy in utero is only a few
weeks / months.
 Three quarters of babies with Down Syndrome will
die in utero .
 Down Syndrome life expectancy for babies and
infants, sees approximately 15% dieing before one
year of age.
 Down Syndrome life expectancy for the next 35% will
be death before 50 years of age.
 Down Syndrome life expectancy for the remaining
50% is more than 50 years of age.
Main causes of shortened Life Expectancy During first
year of life:
 First and foremost, heart problems.
 Second, problems with the digestive
system :
 2a. Esophageal atresia
 2b. Tran esophageal fistula
 2c. Hirsch sprung disease
 2d. Duodenal atresia
Cytogenetic disorders involving
sex chromosomes :
 Two factors are peculiar to the sex chromosomes : -
1. Lyonization or inactivation of all but one X
chromosomes and
2. The modest amount of genetic material carried by
the Y chromosomes
Lyon hypothesis
Only one of the X chromosomes is genetically active
2. The other X of either maternal or paternal origin
undergoes heteropyknosis (condensed) and is
rendered inactive
3. Inactivation of either maternal or paternal X occurs
about the 16th day of embryonic life and
4. Inactivation of the same X chromosomes persists in
all the cells derived from each precursor cell.
1.
Cont..
*** Recent studies shows that many genes escape X
inactivation.
At least some of the genes that are expressed from both
X chromosomes are important for normal growth and
development.
e.g ; patients with monosomy of the X chromosomes
(Turner syndrome: 45,X) have severe somatic and
gonadal abnormalities. Because, if a single dose of X –
linked genes were sufficient, no detrimental (harmful)
effect would be expected in such cases.
Cont..
 Although one X chromosome is inactivated in all cells
during embryogenesis, it is selectively reactivated in all
cells during oogonia before the first meiotic division.
Thus, it seems that both X chromosomes are required
for normal oogenesis.
 Y chromosomes :
 both necessary and sufficient for male development
 Presence of single Y chromosomes determines the
male sex.
 Gene that dictates testicular development has been
located on the distal short arm.
Cont…

With this background, we review some features that
are common to all sex chromosomes disorders : 1. Chronic problems relating to sexual development
and fertility
2. Difficult to diagnose at birth, many are first
recognized at the time of puberty
3. In general, the higher the number of X
chromosomes, in both male and female, the greater
the likelihood of mental retardation.
Tunner’s syndrome
 Results from complete or partial monosomy of the
X chromosomes and is characterized primarily by
hypogonadism in phenotypic females
 It is a sex chromosomal aneuploidy here a female
has lost an X chromosome.
 Frequency : 1 in 2000 liveborn females
 Karyotype: 45 X (57%)
29% mosaics (45,X with 1 or more
karyotypically normal or abnormal cells type
14 % -- structural abnormalities of X
chromosomes
Cont…
 99% of 45,X conceptuses are nonviable so many tests
(PCR) shows that the prevalence of mosaic Turner
syndrome increases to 75%.
 In patients who are truly 45, X orin whom the
proportion of 45,X cells is high, the phenotypic
changes are more severe than the mosaicism.
Clinial features
 The disorders may be recognized at the birth.
 A newborn presents with lymph edema of the dorsum
of hand and feet's, and loose skin folds at the nape of
neck.
 An older children will have short stature ,short webbed
neck and low posterior hairline.
 Ears are anomalous and prominent.
 The palate is high arched and mandible is small.
 Chest is broad shield like with widely spaced
hypoplastic nipples.
 There is carrying angle at elbow.
 The fourth metacarpals and metatarsals are short.
 At puberty sexual maturity fails to occur.
 Adult stature is less than 145 cm .
 Associated congenital anomalies are:
 Kidneys : horse shoe kidneys, double or cleft renal
pelvis.
 Heart : coarctation of aorta
 Ears : hearing defective
 Ovarian dysgenesis
 Intellectual development is normal.
MANAGEMENT AND TREATMENT
 Cardiac evaluation including blood pressure and
ECHO is recommended as the base line and then every
year.
 Height should be monitored .
 If the growth is not proper the growth hormone
therapy is useful and may increase the final height by
8 to 10 cm.
 Counseling regarding the behavioral problems due to
short stature ,amenorrhea and sterility is the integral
part of management .
 Yearly TSH monitoring should begin from 10 yrs of
age.
 Ovarian hormone replacement should be
started at age of 14 yrs .To start with
conjugated estrogen (0.3 mg/dl) or ethinyl
estradiol (5-10 microg/dl) is used for
3 to 6 months ; then increased to 0.625 to
1.25 mg (conjugated estrogen) or 20 to 50
microg/dl (ethinyl estradiol). After 6 month
to 1 year ,cyclical therapy with estrogen and
progesterone is started.
 Regular audiometry should be done in adults or earlier
if indicated .
 Evaluation of renal malformation by USG at first
contact should be done .
 Prophylactic gonadectomy in tunner’s syndrome due
to chances of gonadoblastoma.
Klinefelter Syndrome
 Defined as male hypogonadism that occurs when
there are two or more X chromosomes and one or
more Y chromosomes
 It is numerical sex chromosomal abnormalities
(aneuploidy)
 Here a male with extra X chromosomes .
 Frequency is about 1 in 500 live births.
 It can rarely be diagnosed before puberty, because
the testicular abnormality does not develop before
early puberyt.
Cont…
 Classic pattern of Klinefelter syndrome is
associated with a 47,XXY (82%) karyotype
 This results from the nondisjunction during the
meiotic division in one of the parents.
 Maternal nondisjunction at the first meiotic
division is more common than paternal first
meiotic division .
 There is no phenotypic difference between those
who receive the extra X chromosomes from their
father or from mother.
Clinical features
 Small testis
 Poorly developed secondary sexual
characteristics –the growth of the pubic and
the facial hair is often late .
 Gynecomastia
 Infertility
 May be mild reduction in verbal skill, language
difficulty, attention deficit, as well as children
has psychosocial ,learning or school
adjustment problems with hypogonadism,
small testis ,infertility and gynecomastia.
MANAGEMENT AND TREATMENT
 This includes behavioral and psychosocial
rehabilitation .
 Testosterone therapy should be started in middle to
late adolescence with monitoring of level.
 Testosterone enanthate is used in the dose
200 mg /day every 10 to 24 days IM(adults)
 In adolescents -100 mgevery 10 to 14 days.