Causes of Malformations(Teratogenesis or

Dismorphology)? ??

Presented by Dr Sadatinejad, Seyyed Mohsen,student of Medicine from Iran,Kashan 19/12/2012

Birth defect

Congenital malformation

Congenital anomaly

(Hereditary) abnormality

Types of Abnormalities :

• Malformation• Disruptions• Deformations• Syndromes

• Minor anomalies• Major anomalies

Principles of Teratology

- پاسخ )آسیب پذیری( جنین و مادر به عامل تراتوژن1 - مرحله تکاملی جنین2

)Developmental stage at the time of exposure(- دوز و مدت زمان تماس با عامل تراتوژن3

(Dose and duration of exposure to a teratogen)- طریقه عمل تراتوژن : تغییرات در سطح سلولی و مولکولی4- نتیجه تراتوژن : مرگ، ناهنجاری، عقب ماندگی رشد، بیماری های 5

عملکردی

Hereditary )Genetic( causes 15-18%Environmental factors 7-10%Multifactorial 25%Unknown 50%

First week )Resistant period( Embryonic period

Maximum susceptibility )organ morphogenesis(

Fetal Period Lowered Susceptibility )functional derangement(

Genetic factors- اختالالت تعدادي كروموزوم 1•

)Numerical Chromosomal Anomalies()Polyploidyالف) پلي پلوئيدی (•

Triploidy 69 يك تخمك هاپلوئيد با دو اسپرم یاتخمک دیپلوئید با یک اسپرم

Tetraploidy 92 اولين كليواژ

)Aneuploidyب) آنوپلوئيدی (•

تريزومی

)Patau syndrome (13تريزومي

)Edwards syndrome (18تريزومی (Down syndrome سندرم داون )21تریزومی

(Klinfelter syndrome-XXYسندرم كالين فلتر)Triple X )Superfemale(

مونوزمی )Turner syndrome- XOسندرم ترنر(

Patau Syndrome

1/20000

cleft-lip-baby

Edwards Syndrome

1/5000

Maternal nondisjunction (95%)MosaismTranslocation

Down syndrome

• Monosomy• Nondisjunction in sperm

80%• Struc X• Nondisjunction in mitosis

(Mosaism)

ناهنجاري هاي ساختماني كروموزوم - 2••)Structural Chromosomal Anomalies(

• Isochromosome• Crossing over :

• Translocation21,13,14, 15 in Down syndrome

• Partial Deletion Cri du chat 5)microcephal, mental, cardiovas(

• Microdeletion Angelman 15 )speech, mental, movement( Prader- willi 15 )fatty, mental, hypogonad(

• Inversion

- ناهنجاري هاي حاصل از جهش ژنی 3•)Gene Mutation Anomalies(

• Marphan syndrome• Crigler-Najjar syndrome• Roberts syndrome• Alport syndrome• Aarskog-Scott syndrome• Savant syndrome• treacher-collins syndrome• Niemann–Pick disease• Cystic Fibrosis• DMD

Environmental factors

• Infectious Agents (& other disease)

• Drugs Agents (& Hormonic Agents)

• Chemical Agents

• Physical Agents

• A( Viral infections• Rubella virus )German Measles( سرخجه ویروس

1month-From placenta- atrioventricular septsl defect, cataract. Weight ↓

• Cytomegalovirus)CMV(

From Placenta,Cervix,Vagina )& Lactation( - microephaly, deafness, mental retardation, hepatospleenomegally ,cardiac defect,cerebral calcification, blue spot on skin

• Herpes simplex virus)HSV( From Placenta,Vagina)85%(- Defect in CNS,liver, pancreas,ren,suprarenal glands, infection on skin, Eyes or mouth – no treatment=40-50% death

• Varicella-zoster virus)VZV( مرغان آبلهFirst 3 month-From Placenta- limb hypoplasia & parasis., hydrocephaly. Mental retardation, cataract

• HIV After 35th week- Systematic Chronic

infection)fangus,bacterial,viral,protozoan(

Infectious Agents

Infectious Agents• B( Nonviral infections

•Toxoplasma in each three munth -

death,microcephaly,hydroceohaly,cerebral calcification

•Treponema pallidum Syphilis, rhinitis,eye defect)cataract(,icterus,abnormal teeth,

splenohepatomegaly

ناهنجاری با مرتبط مادری های بیماری• Desease

•Diabetes Coudal disgenesis, death

•PKUmental retardation, microcephaly, cardiac defect

• Nutrient deficiency Iodine deficiency coused cretinism

• ObesityONTD, cardiac defect, …

• Hypoxy

Drugs AgentsCategory X drugs

Category D drugs

Category X drugs

Thalidomide

Aminopterin

methotrexate

Busulfan

Phenytoin

Triazolam

Warfarin

Isotretinoin

Clomiphen

Diethylstilbestro

l

Ethisterone

Norethindrone

Nicotine

Alcohol

Category X drugs Thalidomide

antinauseant drug داروی ضد تهوعlimb defect (Amelia,Meromelia)Cardiac defectGIT atresyOptic & otic defect

Category X drugs Thalidomide

Category X drugsAminopterin MethotrexateBusulfan

Used in chemotererapy Dawerfism Myelomeningocele palate clef Growth retardation ophtalmic defect

Category X drugsAminopterin MethotrexateBusulfan

Used in chemotererapy Dawerfism Myelomeningocele palate clef Growth retardation ophtalmic defect

Category X drugsPhenytoin

Antileptic drug microcephalyGrowth & mental retardationpalate clefFinger & nail HypoplesiaSkull defect

Category X drugsWarfarin

Anti couagulant drug Mental retardation microcephaly optic n. atrophy Fetal bleeding

Category X drugsClomiphen

Non-steroidal drug Used for stimulus ovulation

Maybe Malformatin

Category X drugs

Retinoids (vitamin

A)Used for Cystic akne

severe craniofacial defects

cardiac defects

neural tube defects )NTD(

Palate cleft

tretinoin (Retin-A)

isotretinoin, 13-cis-retinoic acid

Category X drugs

Nicotine

Mental retardation Wheight loss Fetal Hypoxy Premature Parturition

Category X drugs

Alcohol

Fetal Alcholic Syndrome (FAS) Mental retardation microcephaly Cardivascular defect Limb & Face malformation Hairsutism

Category D drugs

Tetracycline

doxycycline

Streptomycin

Phenobarbital

Pentobarbital

Valsuroic acid

Diazepam

lorazepam

Lithium

Hydrochlorothiazid

e

Category D drugs

Phenobarbital & Pentobarbital

paliative drug

Fetal malformation

Category D drugs

Diazepam, Lorazepam ,

Chlorodiazepoxide

antianxiety drug palate & lip clef specially in first 3 munth

Category D drugs

Lithium ,Phenothiazine

Antiedepressive

CardioVascular defect

Chemical Agents(heavy metals)

Organic mercury

Blindness, deaf, cerebral pulsy (c.p)

Leadmental retardation, death of fetus

Poly chlorin biphenyil & Pentobarbital mental retardation, gingiva hyperplasia, exophthalmos, skull calcification, brown pigment in skin

Potassium iodideused as contrastment substance. mental retardation, goiter

Physical AgentsIonizing Radiation

Acute high dose (over 250 rads)

Microcephay,spina bifida,palate cleft, limb defect

Hyperthermiaanencephaly,spina bifida, mental retardation,

facial malformation, cardiac defect, limb defect

Male-mediated Teratogenesis

Chromosomal defects & Mutation in germ cells

Environmental agent : transmission of paternal mediated toxicity through seminal fluid

Ultrasonography

Maternal Serum Screening )AFP,hCG(

AFP : Trisomy↓- NTD,GIT atresia,amniotic band↑

Amniocentesis

Chorionic Villus Sampling )CVS(

Prenatal Diagnosis

Fetal Transfusion

Fetal Medical Treatment

Fetal Surgery

Stem Cell Transplantation and Gene Therapy

Befor 18th week )activation of immune system(

Fetal Therapy