Basic Medical Education Programme

Gadjah
CONGENITAL MALFORMATIONS.
School of Medicine
Mada University

dr. E. Suryadi, SU

1
 conception
cleavage
Gametogenesis Ovum/
spermatozoo
Zygot
Meiosis adult
Implantation

Blastula
puberty organogenesis
Reproductive
critical period
cycle Critical period
Embryo
pregnancy
child

fetus

infant
neomate partus/
delivery
mitosis
 INTRODUCTION
CONGENITAL MALFORMATION (CM) :

 Are anatomical abnormalities

present at birth
 May be macroscopic or microscopic
 On surface or within the body

3
TERATOLOGY
 Is the branch of embryology which
deals with abnormal development and
Congenital Malformation (birth defect)

HERMAPHRODITISM
 Errors in sex development may result in
various degree of intermediate sex
4
EPIDEMIOLOGY

 Annually, approximately 3-5% of live

births are born with birth defects.
 Defects may be anatomical or
physiological.
 Medications are uncommon causes,
accounting for 1-3% of birth defects.

5
 Birth defects are found about 1 in 33 babies
born in US
 Birth defect are leading cause 20% of infant
mortality in US
 Birth defects are the fifth leading causes of
years of potential life lost and contribute
substantially to childhood illness and long term
disability
 The cause of about 50-60% of all birth defect is
unknown
 Evaluation of environment, genetic, dietary and
personal risk factor are important
6
ETIOLOGY
 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%)
7
 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
8
 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 Turner’s syndrome or
ovarian dysgenesis
9
TURNER SYNDROM

10
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 for gametogenesis
 Autosomal trisomy
 21 trisomy (Down’s syndrome) 1 : 600
 18 trisomy (Edwards’s syndrome) 1 : 3300
 13 – 15 trisomy (Patau’s 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 12
Trisomi 21(Down’s syndrome)

13
 Gambaran klinik Trisomi 21
 Menthal deficiency
 Brachycephaly,
 Flat nasal bridge
 Potruding tongue; simian crease
 Congenital heart defects
 Gastrointestinal tract abnormalities
Trisomy 18

15
Trisomy 15

16
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 17
5. POLYPLOIDY
 Polyploid cells contain multiple of
the haploid number of chromosomes
(I.e : 69, 92)
 A significant causes of spontaneous
abortion

18
 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 19
 Microdeletion or microduplication syndromes
Syndrome Clinical features Chromosome Parental
findings origin
Prader-willi Hypotoni, hypogonadism, short stature, Del 15 q12 Paternal
small hands and feet,…..
Angelman’s Microcephaly, ataxia, severe mental Del 15 q12 Maternal
retardation,…..
DiGeorge Thymic and parathyroid hypoplasia, del 22 q11 Either
cardiac defect, facial dysmorphism,… parent

Velocardialfaci Palatal defects, hypoplastic alae nasi, Del 22 q11 Either

al cardiac defects, speech delay,….. parent

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

Magenis broad hands, mental retardation. parent

Williams Short stature, Hypercalcemia, cardiac Del 17 q 11,23 Either

anomalies, mental retardation,….. parent

Beckwith- Macroglossia, omphalocele, Dup 11 p15 Paternal

Wiedemann hemihypertrophy, hypoglycemia,…
20
Miller-Dieker Dysmorphic face, seizures, severe Del 17 p13.3 Either
parent
 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 21
 Homeobox Mutation

 Waardenburg syndrome: HuP2 gene

 Sympolydactyly : HOX D 13 mutation
gene
 Holoprocencephaly: HPE 3 mutation gene
 Schizencephaly : EMX2 homeobox gene

22
Achondroplasia

23
 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
24
 MALFORMATION CAUSED BY
ENVIRONMENTAL FACTORS

 Teratogen is agents may induce CM when

structures are developing
 Kinds of teratogen
1. Variety of chemical : poisons, drugs,
industrial dyes
2. Infectious agent : rubella, toxoplasmosis,
rickettsia
3. Physical factors : like X-rays and anoxia
4. Mechanical factors : the amnionic fluid
absorbs  mechanical pressures
25
 SENSITIVE OR CRITICAL PERIODS

 During the organogenesis period (from day

15 to day 60)

 This period teratogenic agent may be lethal

or to produce major morphological
abnormalities

26
27
Efek radiasi terhadap embryo dan fetus
 The teratogenic effect of medications varies
temporally.
 That is, the fetus' susceptibility varies
depending on the fetus' apposite critical
periods of development.
 Different organs have different critical
periods, although the interim from gestation
day 15 to day 60 is critical for many organs.
 The heart is most sensitive during the third
and fourth weeks of gestation, while the
external genitalia are most sensitive during
the eighth and ninth weeks.
 The brain and skeleton are always sensitive,
from the beginning of the third week to the
end of pregnancy and the neonatal period. 29
 TERATOGEN MALFORMATIONS
Androgenic Agents
 Ethisterone Varying degrees of masculinization of
 Nonethisterone female fetus ; most have labial fusion
and clitoral hypertrophy
Antitumor Agents
 Aminopterin Wide range of skeletal defect and
malformations of the CNS
 Busolfan Stunted growth, skeletal abnormalities
(Myleran) G – corneal opacities, cleft palate
mercaptopurine
hypoplasia of various organ
 Methotrexate Multiple malformation, especially
skeletal

Thalidomide Meromelie and other limb

malformations, external ear, cardiac30
and gastrointestinal malformations
Thalidomide effect

31
Infectious Agents
 Cytomegaloviruse Microcephaly, hydrocephaly
microphthalmia, microgyria and
mental retardation
 Rubella virus Cataract, chorioretinitis, deafness
microphtalmia and congenital heart
defects

 Toxoplasma gondii Microcephaly, microphthalmia,

hydrocephaly and chorioretinitis

Therapeutic Radiations Microcephaly and skeletal

Malformation
32
Three components of typical
teratogenic exposure leading to
CM

 Hereditary predisposition to a
malformation
 Hereditary predisposition to the effects
of a given teratogen ( genetic
susceptibility)
 Administration of the teratogen at a
vulnerable period embryogenesis.

33
Cellular Sites of Action of Various Dysmorphogenic Drug
34
 SIX MECHANISM THAT CAN CAUSES
CM (PATTEN)
1. Too little growth
2. Too little resorption
3. Too much resorption
4. Resorption in the wrong location
5. Normal growth in abnormal position
6. Local overgrowth of a tissue or structure

35
 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
Organogenesis Important defects
Exogenous and
multifactorial
actions Metabolic Malformations
Fetus anomalies
genital system
nervous system

Normal neonate Malformed neonate

36
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
Kejadian CM berdasar organ
Prevalence of birth defect in
IVF & ICSI

39
Prenatal diagnostic

 USG examination

 Amniocentesis

 Villi-chorion biopsy
Prevention
 Marriage counseling
 Prenatal counseling and
diagnostic
 Education
 Consume folic acid
 Eat a healthy diet
 Exercise regularly
 Avoid smoking’
 Avoid alcohol
 Avoid illicit drugs
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
Abnormal Development of
Uterus
Others abnormal of female genital
organ
 Absence of the vagina and uterus: This result
from failure of the sinovaginal bulbs to develop
and form the vaginal plate
 Vaginal atresia: failure of canalization of the
vaginal plate results in atresia of the vagina.
Failure of the inferior end of the vaginal plate to
perforate results in an imperforate hymen
 Pseudohermaproditism: female
pseudohermaproditism usually result from
congenital adrenal hyperplasia
 Dysgenesis ovarii : in Turner syndrome
 Pada organ genital masculina

 Male  Epispadia
pseudohermaproditisme  Bifid penis
 Androgen insensitivity  Micropenis
syndrome
 Cryptorchidism
 Mixed gonadal dysgenesis
 Ectopic testis
 Hypospadias
 Congenital
inguinal hernia

47
Differential diagnosis of persons with ambiguous external genitalia 48
Ectopic testis
Tempat testis diluar yang seharusnya yaitu:
 di canalis inguinalis;
 di annulus inguinalis profundus;
 di annulus inguinalis superficialis;
 medial proximal femur;
 dorsal scrotum;
 luar dari aponeurosis m. obliquus externa
abdominalis
Hernia inguinalis congenital

 Hal ini disebabkan adanya hubungan

yang persisten antara cavum
peritoneum dengan cavum vaginale
scroti atau persisten processus
vaginalis
Hydrocele

 Karena adanya hubungan antara

prosesssus vaginalis dan cavum
peritonei pada masa perkembangan
sehingga memungkinkan adanya
cairan yang berasal dari cavum
peritonei masuk kedalam cavum
vaginale disekeliling testis (hydrocele)
, apabila prosessus vaginalis persisten
maka dapat pula menimbulkan
hydrocele pada funiculus spermaticus.
TERIMA KASIH

52