Genetics Diseases :

Chromosomal disorder

dr.Yanuarita Tursinawati ,M.Si,Med

Fakultas Kedokteran
Universitas Muhammadiyah Semarang
2017
 Chromosomal mutation
Chromosomal mutation can be :

1.Numerical
 Autosomal (Down syndrome, Trisomy 13, Trisomy 18)
 Sex chromosom (Turner syndrom, Klinefelter syndrom)

2. Structural
 Deletion (Cri du chat syndrome, Wolf Hirschhorn syndrom)
 Duplication (Charcot Marie Tooth disease type 1A)
 Translocation (Down syndrome, Leukemia)
 Inversion , Rings, Isochromosom
 A.Numerical Chromosomal mutation
A.1. Autosomal chromosom disorder
a. Trisomy 13 (Patau's syndrome) 47,XX+13

– Very severe conditions of Trisomy caused by the presence

of an extra copy of genetic material on the 13th
chromosome.
– Incidence 1 in 5000 live birth
– Very poor prognosis, with most affected infants dying
during the first days or 4 days due to the presence of
cardiac defects, associated with poor brain stem control.
– Severe learning difficulties.
– Approximately 10% of cases are caused by mosaicism or
unbalanced rearrangements, particularly Robertsonian
translocations in cases of Patau syndrome.
– In a family with non-translocation trisomy 13, recurrence
risk is very low and almost unknown.
 Patau Syndrome

Adam Fabumi
Penderita Trisomi
13
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b. Trisomy 18 (Edward's syndrome)
47,XX+18 or 47,XY+18

 Chromosomal disorder caused by the presence of

an extra copy of genetic material on the 18th
chromosome.
 Incidence 1 in 3000 live birth. The incidence
increases as the mother's age increases .
 The syndrome has a very low rate of survival,
resulting from heart abnormalities, kidney
malformations, and other internal organ disorders,
hearing loos, Rocker bottom feet.
 Those babies who are liveborn, 30% die in the first
month of life and 90% die by 12 months.
Edward Syndrome
 c.Trisomy 21(Down Syndrome)

 Down syndrome is a chromosomal

disorder caused by the presence of an
extra copy of genetic material on the
21st chromosome.
 Incidence 1 in 800 live birth
 Three types of chromosomal DS:
1. Classical Trisomy 21 (95%)
2.Translocation trisomy, Robertsonian
translocation (3-4%)
3. Mosaic Trisomy 21 (1-2%)
 Type of DS
1. Trisomy 21 (classic Down
Syndrome 47 ,XX, +21
– Caused by an error in cell division
(nondisjunction) in the egg or sperm formation 
meiotic nondisjuntion  aneuploidy
– 94 % of DS is classical DS
– Etiology of Down syndromes :
1. 90% coming from nondisjunction in the
maternal gamete
2. 10% coming from nondisjunction in the
paternal gamete
Trisomy 21 (classic Down Syndrome)
 2. Translocation DS / Familial Down syndrome.

 46, XX, t(14,21)(q10,q10)

 4 % of total DS
 A Robertsonian translocation occurs
when one chromosome 21 attaches to
another chromosome,such as 14 or
13, 15, or 22

A single new chromosome

Robertsonian Translocation

Translocation 14;21
 3. Mosaic Trisomy 21
– karyotype: 46, XY / 47, XY,+21 or 46, XX / 47, XX,
+21.
– 2 % of total DS

– Individuals have some cells with the typical number of

chromosomes (46) and some cells with an extra
chromosome 21
 How can mosaicism occurs?
• All of the cells in our body come from a single
cell, the fertilized egg or zygote  divide 
make an identical copy of itself.
• Trisomy mosaicism can occur in one of two
ways:

1. In an abnormal fertilized egg with 47

chromosomes, one of the cells may lose the
extra chromosome at cell division, leaving 46
chromosomes in that cell  46 & 47 chr (+)

2. In a typical zygote with 46 chromosomes , one of

the cells may added the extra chromosome at
cell division  46& 47 (+)
CLINICAL EXAMINATION (1)
• Head & face : microcephaly, short neck, flat
occiput (brachycephaly),small ear, flat nasal bridge”,
hypertelorism, upward slanting palpebral fissures 
mongoloid face.
• Eye : Brushfield spots in the iris (pathognomonic,
detectable in blue eyes).
• Mouth : macroglossia, glossitis exfoliativa
(geographic tongue), frequently open mouth, narrow/
high arched palate.
• Hand : short and broad, clinodactyly of the 5th
finger, simian crease on palm.
• Feet : flat feet, sandals gap (first toe set apart from
the others by a gap).
• Severe hypotonia
 CLINIC PICTURES
Upslanting
palpebral fissures

Small mouth
Large tongue
CLINIC PICTURES

Simian crease

Sandal gap
 Psycho-motor delay
• Hypotonia at birth (hold his head at 6 mo, sits at age 1 yr, walks at
age 2 yrs)
• Mental retardation, not obvious in the infant, will soon become
manifest. A broad range of intellectual ability with IQ scores ranging
from 25 to 75
• Children's behaviour  cheerful / happy kid; language difficulties;
like to play.
• Seizures (in 3% to 9%, as compared to 1% in the general population).
• Psychiatric disorder (18-38% ): Attention Deficit Hyperactivity
Disorder (ADHD)
 The 21st Chromosome and Down Syndrome

- 21st Chromosome contain 200-250 genes

- Extra number chromosome 
overexpression of involved gene  extra
protein product.
- The Down Syndrome Critical Region
only a small portion of the 21st chromosome
actually needed to be triplicated to get the
effects seen in Down syndrome
 Gene involved in 21st
Chromososme
• Superoxide Dismutase (SOD1)-- premature aging
and decreased function of the immune system,the
Alzheimer's type or decreased cognition
• COL6A1 -- heart defects
• ETS2 -- skeletal abnormalities
• CAF1A -- detrimental to DNA synthesis
• Cystathione Beta Synthase (CBS) -- disrupt
metabolism and DNA repair
• DYRK -- mental retardation
• CRYA1 -- of cataracts
• GART -- disrupt DNA synthesis and repair
• IFNAR -- interfere with the immune system as well
as other organ systems
 Complication and other diseases
• Heart (40%): atrioventricular septal defect (10 %);ventricular
septal defect (10 %); patent foramen ovale (5 %); persistence
of ductus arteriosus (5 %).
• Digestive (10 %), duodenal stenosis (1/3 of duodenal stenosis
are found in trisomy 21patients), imperforate anus.
• Ocular cataract (congenital or Acquired), astigmatism,
myopia, strabismus, congenital glaucoma, nystagmus.
• Hematologic: acute leukemia
• Immunological: tuberculine hyporeactivity, immune
deficiency.
• Metabolic: hyperuricemia; abnormal glycemia; increased
TSH (frequent); hypo or hyper thyroidy.
• Skin ; xerosis , hiperkeratosis, vitiligo, follikulitis, abces,
recurrent skin infection
• Ear : Hearing loss , Otitis media
 Diagnosis
By Physically appearence and Karyotyping
 Treatment
• No cure exists for Down syndrome.
• Physical therapy and speech therapy

Quality

Scottish award-winning film and TV actress

Paula Sage receives her BAFTA award with
Brian Cox.
 Prognosis
 Depend on quality of intervention and healthy care
In the United States in 2002, showed an average
lifespan of 49 years  variations between ethnic and
socio-economic groups.
• prognosis can be impaired by:
1. The extreme susceptibility to infections.
2. Malformations, cardiac malformations in particular.
3. Acute leukemia (in 1 % of trisomy 21
infants/children,
 Causes of death  chronic neurodegenerative
diseases
 Prenatal Screening
• First Trimester Screening

1. Optional non-invasive evaluation that combines maternal age, a

maternal blood screening test ( lower PAPP-A and higher free HCG )
and with an ultrasound  to identify risk for Down Syndrome.

2. Performed between 11th till 14th week of pregnancy.

3. A positive test means you have a 1/100 to 1/300 chance of experiencing

one of the abnormalities  High risk

4. Abnormal result warrant additional testing for making a diagnosis such

as CVS or amniocentesis.
 Second Trimester screening

1. Performed between 15th till 20th week of pregnancy

2. Measure a maternal blood (AFP + HCG= double test, if

AFP+HCG+unconjugated estriol = triple test)  AFP↓, estriol↓, total
HCG↑
 Serum markers for Down's syndrome
Marker Expected result 1st 2nd
trimester trimester
Maternal age  
Nuchal translucency 
Pregnancy Associated Plasma Protein A (PAPP-A) Lower 
Free beta-human chorionic gonadotrophin (fβ- Higher 
HCG)
Total HCG Higher 
Alpha-fetoprotein (AFP): Lower 
Unconjugated oestriol (uE3): Lower 

Inhibin-A: Higher 

Adapted from: Malone FD, Canick JA, Ball RH, et al. First-trimester or second-trimester

screening, or both, for Down's syndrome. N Engl J Med 2005;353:2001-2011

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Ultrasound –Prenatal Screening

Nuchal translucency and absent Nasal bone is only predictive

finding, NOT diagnostic for Down syndrome.
 Fetal nuchal translucency
• Nuchal translucency is the sonographic appearance of
subcutaneous accumulation of fluid behind the fetal
neck in the 1st trimester of pregnancy.
• Between 11 weeks and 13 weeks + 6 days.
• Prospective studies have demonstrated that NT
screening can identify more than 75% of fetuses with
trisomy 21 for a false positive rate of 5%.
• Increased nuchal translucency reflects fetal heart
failure and defect in lymphatic drainage, and is
typically seen in any serious anomaly of the heart and
great arteries, and strongly associated with a
chromosomal abnormality.
• Specific standards have been set for nuchal
translucency measurement.
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 Prenatal Diagnosis
• Chorionic Villus sampling
1. Performed at 10-12th w of gestation
2. Withdrawl the placenta
3. Misscariage risk 1%
4. Result available after 1-2 week
 Amniocentesis
1. Performed at 14-18th w of gestation
2. Withdrawl the amniotic fluid
3. Misscariage risk 0,5 %
4. Result avaliable after 2-3 week
 Reccurence Risk of DS
Type of Down Syndrome Recurrence Risk

Classical DS 1 % = 1/100
Above 35 yo =age related risk

Translocation DS - Parents Normal karyotype : 1%

- Parents carier balanced traslocation
t(14,21) Maternal = 10-12%
Paternal = 2-3%
-Parents carier balanced translocation
t(21,21) paternal or maternal = 100 %

Mosaicm DS Maternal Age related risk

 B.Structural Chromosomal mutation
Cri Du Chat syndrom
• Known as “ Cat Cry Syndrome” or “ 5p monosomy”
• The incidence is 1 in 50.000 live births  rare
• Arises from a partial terminal or interstitial deletion of
the short arm of chromosome 5 (5p).
• Etiology :

1. 90 % sporadic, randomly, de novo deletion during the

formation of reproductive cells (eggs or sperm)  not
inherited

2. 10 – 15 % from the parent who carries a balanced

translocation
Deletion of Chromosome 5
 Cytogenetics
• Multigenic
• Researchers have found two
critical regions for CdC
– Cat-like cry localized at
5p15.3
– Facial dysmorphisms and
psychomotor/mental
retardation localized at
5p15.2
 Clinical exam, cognitive and behaviour
of cri du chat syndrome
• Usually small at birth, and may have respiratory problems.
• The larynx doesn’t develop correctly, which causes the signature
cat like cry.
• Difficulty to breath and swallow  small larynx
• Dysmorphology : small head and jaw , wide eyes, microcephaly,
hypertelorism, down slanting palpebral fissure, flat nasal bridge,
low set ears, down turned mouth, short finger, single palmar
crease. Weight and poor growth.
• Poor muscle tone (hypotonia)
• Frequently has Cardiac defect
• Severe cognitive impairment, speech and motor delays and
severe mental retardation.
• Behavioral problems such as hyperactivity, aggression, tantrums
and repetitive movement
Cri Du Chat children