KELAINAN KONGENITAL GENETIK

Oleh : E. Suryadi
FK UGM YOGYA
 ETIOLOGY congenital anomaly
Genetic: gene mutation (7-8%), chromosome
aberration (6-7%)
Environment (7-10%)
chemise: drug
biology: virus
physic: radiation
mechanic: be tied umbilical string
Multifactor: interaction between genetic and
environment (20-25%)
Unknown (50-60%)
 MEKANISME: Disturbance of Polypeptide
Synthesis
Congenital anomaly= birth defect abnormality in
organogenesis is caused by abnormality of mitosis,
differentiation, morphogenetic of cells or tissues
Genetranscriptiontranslation -- epigenesis
- chromosome aberration
- mutation
Protein fungsional/structural
Enzyme metabolism process
Receptor induction
Extra-cellular proteins induction interaction
Hormone stimulation
Nutrition metabolism resources
 Kinds of birth defect

Malformation: results from an intrinsically

abnormal development process (genetic).

Deformation; result from mechanical forces

Disruption; result from an extrinsic

breakdown an originally normal (teratogen).
 Types of
Problems in
morphogenesis

Poor Unusual Breakdown

Formation Forceson of Normal
of Tissue normal Tissue
poor tissue
formation
mechanical Destruction
Malformation
Deformation Disruption
Multiple Single
defect defect
 GENERAL DIAGNOSIS AND
TREATMENT
Confirm and counsel
-an understanding of how the altered
structure come
-how method to assist the child
-the mode of etiology and genetic counseling
-the degree of abnormality
Macam berdasar penyebab genetik
KeLainan genetik kromosomal (aberasi kromosom):
Kelainan Jumlah kromosom : nondysjuntion
selama meiosis
Kelainan struktur kromosom: delesi, translokasi
Kelainan gen: mutasi sel gamet: sperm/oosit
Gen tunggal: dominan/resessif pada
autosom/gonosom
Gen multiple/polygen: erythroblastosis fetalis
(Rh)
Gangguan perkembangan Signaling Pathways
(homeobox gen mutation)
CHROMOSOMAL ABNORMALITIES
About one of 200 new born infants

Two kinds of changes : numerical and

structural

Changes in chromosome number represent

either aneuploidy or polyploidy

Aneuploidy, any deviation from the diploid,

may be hypodiploid or hyperdiploid
NUMERICAL CHROMOSOMAL
ABNORMALITIES
1. MONOSOMY
Embryos missing a chromosome usually
die
About 97 % at Embryos Lacking a sex
chromosome also die and 3% (about 3 in
10.000 new born female) have
characteristics of Turners syndrome or
ovarian dysgenesis
 TURNER SYNDROME
1. short stature 97
2. primary amenorrhea 96
3. sterility 99
4. sexual infantilism 95
5. hypoplastic, hyperconvex nails 73
6. low nuchal hairline 73
7. short neck 71
8. pigmented nevi 60
9. shield chest 59
10. cubitus valgus 58
2. TRISOMY
If three chromosomes are present instead of the
usual pair
Cause of trisomy is non disjunction during
meiosis
Autosomal trisomy
21 trisomy (Downs syndrome) 1 : 600
18 trisomy (Edwardss syndrome) 1 : 3300
13 15 trisomy (Pataus syndrome) 1 : 5500
Sex chromosomal trisomy
47, XXX female 1 : 1000 mentally retarded
47, XXY Male 1 : 500 klinefelter syndrome
47, XYY Male 1 : 1000 personality disorder
Trisomi 21

12
 Gambaran klinik Trisomi 21
Menthal deficiency
Brachycephaly,
Flat nasal bridge
Protruding tongue; simian crease
Congenital heart defects
Gastrointestinal tract abnormalities
Trisomy 18

14
Trisomy 13

15
3. TETRASOMY AND PENTASOMY
Have four or five sex chromosome mental
retardation and physical impairment
4. MOSAICISM
Person with this condition have two or more cell
lines with different karyotypes (46 XX / 45 x 0 /
47 XXX)
The autosomes and the sex chromosome may
be involved
Usually the malformation are less serious
Usually arises by non disjunction during early
cleavage division
5. POLYPLOIDY

Polyploid cells contain multiple of the haploid

number of chromosomes (I.e : 69, 92)

A significant causes of spontaneous abortion

CHROMOSOMAL STRUCTURAL
ABNORMALITIES
Result from chromosome breaks
Induce by various environmental factors
The type of abnormality which result depends
upon what happens to the broken piece
Kind of structural abnormalities
- Translocation - duplication
- deletion - isochromosome
- a ring chromosome
 Microdeletion or microduplication syndromes
Syndrome Clinical features Chromosome Parental
findings origin

Prader-willi Hypotoni, hypogonadism, short Del 15 q12 Paternal

stature, small hands and feet,..
Angelmans Microcephaly, ataxia, severe mental Del 15 q12 Maternal
retardation,..
DiGeorge Thymic and parathyroid hypoplasia, del 22 q11 Either
cardiac defect, facial dysmorphism, parent
Velocardialf Palatal defects, hypoplastic alae nasi, Del 22 q11 Either
cardiac defects, speech delay,.. parent
acial

Smith- Brachycephaly, prominent jaw, short Del 17 p11.2 Either

broad hands, mental retardation. parent
Magenis
Williams Short stature, Hypercalcemia, cardiac Del 17 q Either
anomalies, mental retardation,.. parent
11,23
Beckwith- Macroglossia, omphalocele, Dup 11 p15 Paternal
Wiedemann hemihypertrophy, hypoglycemia,

Miller- Dysmorphic face, seizures, severe Del 17 p13.3 Either

developmental delay, cardiac parent
Dieker 19
anomalies,
 The detection of chromosome
abnormalities during life cycle
Pre-implantation genetic diagnosis
Fertilization to 12 weeks gestation
12 weeks gestation to term
The neonatal period
Early childhood development
Puberty and sexual development
Problems in fertility and reproductive failure
Adulthood
 Taking (neonates)
Lymphocytes ( peripheral blood). The tissue of
choice for initial studies in most cases and
cord blood, a useful substitute for peripheral
blood if abnormality suspected prior to
delivery
Bone marrow. Rarely be used, but can provide
a very rapid result.
Taking.( stillbirths, intrauterine deaths, termination
> 12 weeks gestation with an intact fetus)

Cardiac blood. Can be taken without interfering with

post-mortem studies
Skin, muscle and amnion. Need to be taken in
conjunction with post mortem studies. Careful
dissection minimizes the risk of maternal cell
contamination.
Placenta ( long-term culture and direct
preparations). Limited success rate, but interphase
cells are good for rapid fluorescent in situ
hybridization (FISH) confirmation of aneuploidy
Taking.. (fetal abnormality detected by second
or third trimester ultrasound)
Fetal blood (cordocentesis). Fast and reliable,
sampling only available in specialist centered.
Direct preparation produce fast result.
Placental biopsy (placentesis). Potential
problems with confined placental mosaicism
(CPM)
Amniotic fluid. Slow. Limited value on its own.
 Homeobox Mutation
Homeobox= gen yang aktif hanya ketika masa
embryogenesis yang berperan dalam morphogenesis
atau disebut morphogens yang mempengaruhi sel
disekitarnya (induksi-interaksi) .
Waardenburg syndrome: HuP2 gene
Sympolydactyly : HOX D 13 mutation gene
Holoprocencephaly: HPE 3 mutation gene
Schizencephaly : EMX2 homeobox gene
MALFORMATION CAUSED BY
MUTANT GENES
Rarer than numerical and structural
chromosomal abnormalities

Most mutant genes do not causes CM to

express depend on dominant or recessive
gene

Examples, dominant: achondroplasia and

polydactyly; recessive: congenital adrenal
hyperplasia, microcephaly, and
dentinogenesis imperfecta
HERMAPHRODITISM
= Intersexuality
Early embryo has the potential to develop into
a male and female
Classification :
True hermaphrodites
have both ovarian and testicular tissue

Pseudo hermaphrodites
have testes called male pseudohermaphrodites
have ovaries called female pseudohermaphrodites
 Beberapa istilah pada cacat lahir
Defek sistem tunggal : adalah kelainan pada
bagian salah satu organ sistem tertentu saja.
Asosiasi: kumpulan kelainan pada suatu kasus
tetapi tak cukup konsisten untuk dikatakan sbg
syndrom.
Sekuen: defek awal yang kemudian ditambah
akibatnya sehingga menjadi ganda
Kompleks: adanya pengaruh buruk yang
berakibat kelainan stuktur yang berdekatan
Syndrom: kelainan ganda yang terjadi secara
konsisten.
 Origin of the Normal Abnormal
malformation development development

Dominant or
Point mutation Genetic recessive defect
Chromosomal information
Syndrome of
aberration chromosomal
aberration
Placenta of
mother Embryo
Organogenesis Important defects
Exogenous and
multifactorial
actions Metabolic Malformations
Fetus anomalies
genital system
nervous system

Normal neonate Malformed neonate/ birth

defect
 Some cases of birth defect
Small intestinal atresia/stenosis
Defect of neural tube
Spina bifida
Anencephali
Encephalocele
Orofacial cleft
Cleft palate
Cleft lip
Congenital heart defect
ASD
VSD
Tetralogy of Fallot
. Intersexuality
Prevention
Marriage counseling
Prenatal counseling and diagnostic
Education
Consume folic acid
Eat a healthy diet
Exercise regularly
Avoid smoking
Avoid alcohol
Avoid illicit drugs
 Prinsip penyuluhan genetik

Diagnosis harus ditegakkan

Ditekankan konselor cukup memberi informasi
Penderita atau klien sendiri yang akan
memutuskan
 Keadaan yang sering perlu konseling
genetik
1. menjelang pernikahan: anggota pasangan atau
kedua-duanya mempunyai kelainan genetik, atau ada
anggota keluarga yang menderita, dan perkawinan
keluarga
2 pasangan steril
3. sering abortus berulang, mempunyai anak cacat,
penyakit metabolisme pada anak atau menahun
4. penyakit degenerasi pada remaja
5. adanya pajanan terhadap teratogen
6. adanya kemungkinan kelainan kromosom
 Menegakkan diagnosis
1. anamneses
2. pembuatan silsilah keluarga (pedegree
=genogram)
3. pemeriksaan dismorfologi
4. pemeriksaan anggota keluarga yang lain
5. pemeriksaan dermatoglifi
6. Pemeriksaan kromatin kelamin
7.pemeriksaan kromosom
8. pemeriksaan khusus
9. konsultasi kepada ahli yang terkait.
Cara Diagnosis prenatal pada kelainan
congenital
1. Amniosentesis
2. Biopsi villi khorialis
3. USG
4. fetoskopi
5. Radiografi atau dengan sinar X
 Deteksi carrier dilakukan jika:

1. pengurangan ringan pada suatu enzim

2. ganngguan ringan elektrofisiologi
3. defect ringan pada tulang
4..ganngguan ringan pada alat indera
 Contoh :Deteksi carrier penyakit
terangkai X
Penyakit Kelainan yang ditemukan
Hemofli A Pengurangan faktor
pembekuan darah VIII
Hemofili B Pengurangan faktor
pembekuan IX
Albinisme Ocular Depigmentasi retina dan iris
dalam bentuk bercak
Distrofi muscular Duschenne Kenaikan enzime kinase serum
Diabetes insipidus PENGURANGAN DAYA
PEMEKATAN URIN
 Cara Pencegahan Primer
Menghidari perkawinan calon pasangan risiko
tinggi
Menghidari pembuahan, pada pasangan risiko
tinggi
Diagnosis prenatal pada pasien risiko rekuren,
lalu kemungkinan dilakukan terminasi
kehamilan
 Pencegahan sekunder: menghindari
ekspressi gen(fenotip)
Memberikan obat-obatan/ pengaturan diit
Membatasi atau menghilangkan substrat dalam
makanan: fenilanalin pada fenilketonuria;
menghidari makan laktosa pada penderita
galaktosemia
Memghidari obat tertentu
Penggantian produk tubuh yang kurang
Induksi enzim
Penggantian enzim
 Pencegahan tersier
Operasi
Pemberian obat-obatan symptomatik
Fisioterapi
Penggunaan alat bantu