Cong Mal

8/10/2019 Cong Mal

http://slidepdf.com/reader/full/cong-mal 1/49

Congenital Malformations

• Causes – Genetic/chromosomal

– Enviornmental

• Incidence – 2-3% of neworn !"-#% $ age &

– In "'-#'% of all irth defects cause is un(nown• Genetic/chromosomal

– )'%-)%

• Environmental – )'%

• Multifactorial !genetic * environmental&

– 2'%-2%

8/10/2019 Cong Mal


+eratolog$

• +eratolog$

– ,cience that studies the causes of anormal

develoment

– +he term is derived from the Gree( .teratos

which means monster

– 0irth defects is the numer one cause of

infant mortalit$ !chart&

http://www.marchofdimes.com/aboutus/1529.asp

http://www.marchofdimes.com/aboutus/1529.asp

8/10/2019 Cong Mal


+erms used in 1isease

• ,ign ⇒ oective evidence of a disease

• ,$mtom ⇒ suective evidence of a

disease• ,$ndrome ⇒ refers to a set of s$mtoms

* signs which occur together in the morid

!disease& state

• Etiolog$ ⇒ the stud$ of the cause of

disease

8/10/2019 Cong Mal


+$es of nomalies• Malformations

– 4ccur during formation of structures

• Comlete or artial asence

• lterations of its normal configuration

• 1isrutions – Morhological alterations of structures after

formation

• 1ue to destructive rocesses – 5ascular accidents ⇒ owel atresias

8/10/2019 Cong Mal


+$es of nomalies !cont6&

• 1eformations – 1ue to mechanical forces that mold a art of

fetus over a rolonged eriod of time

• Clufeet due to comression in the amniotic cavit$

• 4ften involve the musculos(eletal s$stem * ma$

e reversile ostnatall$

• ,$ndromes

– Grou of anomalies occuring together with asecific common etiolog$

• 1iagnosis made * ris( of recurrence is (nown

8/10/2019 Cong Mal


,$ndrome e7amles

• C89GE

– Coloomas

– 8eart defects

– tresia of the choanae – 9etarded growth

– Genital anomolies

– Ear anomalies

• 5C+E9I

– 5erterral anomalies !&

– nal

– Cardiac – +racheoesohageal

– 9enal

– :im

8/10/2019 Cong Mal


Environmental factors

• Infectious agents

• 9adiation

• Chemical gents• 8ormones

• Maternal 1isease

• ;utritional 1eficiencies• 8$o7ia

8/10/2019 Cong Mal


Infectious gents• 9uella !German Measles&

– Malformations of the e$e

• Cataract !#th wee(&

• Microhthalmia

– Malformations of the ear !<th wee(&• Congenital deafness

– 1ue to destruction of cochlea

– Malformations of the heart !th

-)'th

wee(&• =atent ductus arteriosis

• trial setal defects

• 5entricular setal defects

8/10/2019 Cong Mal


Infectious gents !cont6&

• 9uella !German measles& – Ma$ e resonsile for some rain

anormalities

• Mental retardation

– Intrauterine growth retardation

– M$ocardial damage

– 5ascular anormalites

– Incidence• ">%- during )st four wee(s

• 22% - th – ?th wee(s

• )3% - <th

– )#th

wee(

8/10/2019 Cong Mal



• 9uella !cont6&

– :a tests ermit detection of virus

– ntiod$ levels can e determined

– In one stud$ ? % of women tested were

immune !n @ #''&

– 5irus infects fetus via the lacenta

• Infection of the child ma$ ersist after irth for anumer of $ears

– Infection can e transmitted to hosital ersonnel

– 5accines are considered safe * effective

8/10/2019 Cong Mal



• C$tomegalovirus – 1isease is often fatal earl$ on

– Malformations• Microcehal$

– Cereral calcifications – 0lindness

• Chorioretinitis

– Aernicterus !a form of aundice& – multile etechiae of s(in

– 8eatoslenomegal$

– Mother as$mtomatic

8/10/2019 Cong Mal



• 8eres ,imle7 5irus – Intrauterine infection of fetus occasionall$ occurs

– Bsuall$ infection is transmitted close to time ofdeliver$

– normalities !rare&• Microcehal$

• Microhthalmos

• 9etinal d$slasia

• 8eatoslenomegal$• Mental retardation

– Bsuall$ child infected $ mother at irth• Inflammator$ reactions during first few wee(s

8/10/2019 Cong Mal



• 5aricella !chic(eno7& – Congenital anomalies

• 2'% incidence following infection in )st trimester

• :im h$olasia• Mental retardation

• Muscle atroh$

• 8I5/I1, – Microcehal$

– Growth retardation

– normal facies !e7ression or aearance of

the face&

8/10/2019 Cong Mal


Infectious gents !cont6&• +o7olamosis

– =rotooa arasite !+o7olama gondii&• ,ources

– =oorl$ coo(ed meat

– 1omestic animals !cats&

– Contaminated soil with feces

• ,$hilis – Congenital deafness

– Mental retardation

– 1iffuse firosis of organs !eg6 liver * lungs&

• In general most infections are $rogenic – 8$erthemia can e teratogenic

• Dever

• 8ot tus * ,aunas

8/10/2019 Cong Mal


9adiation• +eratogenic effect of ioniing radiation well

estalished – Microcehal$

– ,(ull defects

– ,ina ifida – 0lindness cleft alate

– E7tremit$ defects

• 1irect effects on fetus or indirect effects ongerm cells

• Ma$ effect succeeding generations

• void -ra$ing regnant women

8/10/2019 Cong Mal


9adiation

• ,tudies of offsring of Faanese women

who were regnant at the time of the

atomic om e7losions over 8iroshima *

;agasa(i who survived the last

– 2?% aorted

– 2% gave irth to children who did not survive

their first $ear – 2% of the surviving children had

anormalities of C;,

•e6g6 Microcehal$ * mental retardation

8/10/2019 Cong Mal


Chemical agents/1rugs

• 9ole of chemical agents * drugs inroduction of anomalies is difficult to assess – Most studies are retrosective

• 9el$ing on mothers memor$ – :arge H of harmaceutical drugs used $

regnant women• ;I8 stud$ – <'' drugs ta(en $ regnant women

– verage of "/woman during regnanc$ – 4nl$ 2'% of women use no drugs during regnanc$

– 5er$ few drugs have een ositivel$ identified aseing teratogenic

8/10/2019 Cong Mal


1rugs

• +halidomide

– ntinauseant * sleeing ill

– Dound to cause amelia * meromelia

• +otal or artial asence of the e7tremities

– Intestinal atresia

– Cardiac anormalities

– Man$ women had ta(en thalidomide earl$ inregnanc$ !in German$ in )<#)&

8/10/2019 Cong Mal


1rugs !cont6&

• minoterin

– ntagonist of Dolic cid

– ntineolastic agent which inhiits mitosis

– 1efects

• nencehal$

• Meningocele

• 8$drocehalus• Cleft li * alate

8/10/2019 Cong Mal


1rugs !cont6&• nticonvulsants !to treat eiles$&

– 1ihen$lh$dantoin !hen$toin&

• Craniofacial defects

• ;ail * digital h$olasia

• Growth anormalities• Mental deficienc$

• +he aove attern is (now as .fetal h$dantoin

s$ndrome

– 5alroic acid

• ;eural tue defects

• 8eart defects

• Craniofacial * lim anomalies

8/10/2019 Cong Mal


1rugs !cont6&

• +rimethadione !s$ndrome&

– Malformed ears

– Cleft alate

– Cardiac defects

– Brogenital anomalies

– ,(eletal anomalies

8/10/2019 Cong Mal


1rugs !cont6&

• ntis$chotic drugs !maor tranuiliers& – =henothiaine * lithium

• ,usected teratogenic agents

• ntian7iet$ drugs !minor tranuiliers& – MeroamateJ chlordiaeo7ideJ

• ,evere anomalies in ))-)2% of offsring where

mothers were treated with the aove comared to

26#% of controls – diaeam !valium&

• Dourfold ⇑ in cleft li with or without cleft alate

8/10/2019 Cong Mal


1rugs !cont6&

• nticoagulants – Karfarin !6A6 cumadin or cumarol&

• +eratogenic

• 8$olasia of nasal cartilage

• Chondrod$slasia• Central nervous s$stem defects


– troh$ of the otic nerves

• ntih$ertensive agents – angiotensin converting en$me !CE& inhiitor

• Growth d$sfunctionJ renal d$sfunctionJoliogoh$dramniosJ fetal death

8/10/2019 Cong Mal


1rugs !cont&• =ro$lthiouracil

– Goiter


• =otassium iodide

– Goiter – Mental retardation

• ,tretom$cin – deafness

• ,ulfonamides – (ernicterus

• Imiramine !antider6& – :im deformaties

• +etrac$clines – 0one * tooth anomalies

• mhetamines – 4ral clefts

– C5 anormalities

• Luinine

– 1eafness

• sirin – =otentiall$ harmful in

large doses

8/10/2019 Cong Mal


1rugs !cont6&

• Isotretinoin !)3-cis-retinoic acid& – nalogue of vitamin

– 1rug is rescried for treatment of c$stic acne

* other chronic dermatoses – 8ighl$ tertogenic

• 9educed * anormal ear develoment

• Dlat nasal ridge

• Cleft alate

• 8$drocehal$

• ;eural tue defects

• 8eart anomalies

8/10/2019 Cong Mal


9ecreational drugs

• =C= angel dust – =ossile malformations * ehavioral

disturances

• Cocaine-vasoconstrictor ⇒ h$o7ia – ,ontaneous aortion


– Microcehal$ – 0ehavioral rolems

– Brogenital anomalies

– gastroschisis

8/10/2019 Cong Mal


lcohol• 9elationshi etween alcohol consumtion

* congenital anormalities

• Detal alcohol s$ndrome – Craniofacial anormalities

• ,hort aleral fissures• 8$olasia of the ma7illa

– :im deformities• ltered oint moilit$ * osition

– Cardiovascular defects• 5entricular setal anormalites


– Growth deficienc$

8/10/2019 Cong Mal


Cigarette ,mo(ing

• 8as not een lin(ed to maor irth defects

– ,mo(ing does contriute to intrauterine

growth retardation * remature deliver$

– ,ome evidence that is causes ehavioral

disturances

8/10/2019 Cong Mal


8ormones• ndrogenic gents

– ,$nthetic rogestins were used freuentl$ to reventaortion

• Ethisterone * norethisterone – 8ave considerale androgenic activit$

Masculiniation of female genitalia

• 1ieth$lstilesterol – Commonl$ used in the )<"'s * )<'s to revent

aortionN in )<>) determined that 1E, causedincreased incidence of vaginal * cervical cancer inwomen who had een e7osed to 1E, in utero

– In addition high % suffered from reroductived$sfunction

• 4ral Contracetives – :ow teratogenic otentialJ discontinue if regnanc$

susected

• Cortisone-cleft alate in mice !not humans&

8/10/2019 Cong Mal


Maternal 1isease• 1isturances in C84 metaolism !diaetic

mothers& – 8igh incidence of stillirthJ neonatal deaths

– normall$ large infants

– Congenital malformations∀⇑ ris( 3-"

• CardiacJ ,(eletalJ C;, nomalies

• Caudal d$sgensis –

=artial or comlete agenesis of sacral verterae inconuction with hindlim h$olasia

– 8$ogl$cemic eisodes ⇒teratogenic !wh$O&

– 4ral h$ogl$cemic agents ⇒ ma$e

teratogenic

8/10/2019 Cong Mal


8/10/2019 Cong Mal


8$o7ia

• ssociated with congenital malformations

in a great variet$ of e7erimental animals

– In humans OOO

• Ma$e smaller aies e6g6 offsring at high altitude

8/10/2019 Cong Mal


Environmental Chemicals

• Mercur$

– DishJ seed corn sra$ed with mercur$

containing fungicide

• Multile neurological s$mtoms

• :ead

⇑ aortions


– ;eurological disorders

8/10/2019 Cong Mal


=revention of irth defects

• Good renatal care

• Iodine sulementation eliminates mental

retardation * one deformities

– =revent cretinism

• Dolate/Dolic cid sulementation

⇓ incidence of neural tue defects

• voidance of alcohol * other drugs during

all stages of regnanc$

⇓ incidence of irth defects

8/10/2019 Cong Mal


=rinciles of teratolog$• Kere first formulated $ Kilson !)<<&• ,uscetiilit$ to teratogens deend on genot$e

and its environmental interaction• ,uscetiilit$ varies with develomental stage at

time of e7osure – Most sensitive eriod for inducing irth defect is wee(s 3-

? of gestation

• Manifestations of anormal develoment deendon dose * duration of e7osure

• +eratogens act in secific wa$s on develoing cells* tissues to initiate anormal emr$ogenesis• manifestations of anormal develoment ⇒ deathJ

malformationJ growth retardationJ functional

disorders

8/10/2019 Cong Mal


Chromosomal * Genetic Dactors

• ;umerical normalities

– +risom$ 2) !1own s$ndrome&

– +risom$ )?

– +risom$ )3

– Alinefelter ,$ndrome

– +urner ,$ndrome

– +rile ,$ndrome

• ,tructural normalities

• Mutant Genes

8/10/2019 Cong Mal


Chromosomal normalities• Ma$ e numerical or structural

• Imortant causes of congenitalmalformations * sontaneous aortions

• Estimated that '% of all concetions end

in sontaneous aortion * '% of thesehave maor chromosome anormalities

• Most common chromosome anormalities

in aorted fetuses isP – +urner s$ndrome !"J&

– triloid$

– trisom$ )#

8/10/2019 Cong Mal


;umerical normalities

• ;ormal gametes are haloid !n @23&• ;ormal human somatic cell contains "#

chromosomesN 1iloid !2n @ "#&

• Euloid-E7act multile of n

• neuloid-n$ chromosome H that is noneuloid

– dditional chromosome

– Missing chromosome

• Most common cause is nondisunction duringeither meiosis to mitosis

– 9is( of meiotic nondisunction ⇑ with ⇑ maternal age

8/10/2019 Cong Mal


1own s$ndrome !trisom$ 2)&•

E7tra co$ of Chromosome 2) !<%& – Growth retardation

– 5ar$ing degrees of mental retardation

– Craniofacial anormalities

• Bward slanting e$es• Eicanthal folds

• Dlattened facies

• ,mall ears

• Cardiac defects

• 8$otonia

• Most of the time due to meiotic nondisunction

⇑ ris( in women Q 3 !) in )''' ⇒ ) in "''&

8/10/2019 Cong Mal


+risom$ )?•

Mental retardation• Congenital heart defects

• :ow set ears

• Dle7ion of fingers * hands

• Micrognathia

• 9enal anomalies

• ,$ndact$l$

• Malformations of the s(eletal s$stem

• Infants usuall$ die $ age 2 months

• Incidence is ) in '''

8/10/2019 Cong Mal


+risom$ )3•

Mental retardation• 8olorosencehal$

• Congenital heart defects

• 1eafness

• Cleft li * alate

• E$e defects – Microhthalmia

– nohthalmia

– Colooma

• Most infants die $ age 3 months

• Incidence ) in )J'''

8/10/2019 Cong Mal


Alinefelter ,$ndrome

• Dound onl$ in males !">J R most common&• Bsuall$ detected at uert$• I in '' males

• ;ondisunction of homologues• ,terilit$• +esticular atroh$• 8$aliniation of seminiferous tuules

• G$necomastia• Ma$e some mental imairment

⇑ with ⇑ H of chromosomes !e6g6 "?J R&

8/10/2019 Cong Mal


+urner ,$ndrome

• Dound in women with unmista(al$ femaleaearance – sence of ovaries !gonadal d$sgenesis&

– ,hort stature – Keed nec( !freuentl$&

– :$mhedema of the e7tremities

– ,(eletal deformities – 0road chest with widel$ saced niles

– Bsuall$ !"J & missing one chromosome

8/10/2019 Cong Mal


+rile

• =atients with trile are infantile

• ,cant$ menses

• ,ome degree of mental retardation

8/10/2019 Cong Mal


,tructural normalities

• Ma$ involve one or more chromosomes

• Bsuall$ result from chromosome rea(age – 0ro(en iece ma$ e lost

• =artial deletion of chromosome – Cri-du-chat !cr$ of the cat&

• Microcehal$

• Mental retardation• Congenital heart disease

• Man$ other relativel$ rare s$ndromesresult from a artial chromosome loss

8/10/2019 Cong Mal


,tructural normalities• Microdeletions

– ,an a few contiguous genes

• A contiguous gene comle7es

• Can e identified with high resolution chromosome

anding techniues – Genomic imrinting

• Cases that e7hiit differential e7ression

deending if the genetic material is from the

mother or father – ngelman vs6 =rader-Killi s$ndrome

8/10/2019 Cong Mal


Microdeletions• 1eletion on long arm of C )

– ngelman s$ndrome !maternal chromosome&• Mental retardation

• Cannot sea(

• E7hiit oor motor develoment• =rone to unrovo(ed * rolonged eriods of

laughter

– =rader-Killi s$ndrome !aternal chromosome&

• 8$otonia• 4esit$

• Mental retardation

• 8$ogonadism

• cr$torchidism

8/10/2019 Cong Mal


,tructural normalities

• Dragile sites

– 9egions of chromosomes that demonstrate a

roensit$ to searate or rea( under certain

conditions• Dragile s$ndrome


– :arge ears

– =rominent aw – =ale lue irides

– Male !"/2'''& vs6 females !)/"'''&

– 2;1 to 1own s$ndrome as a cause of chromosomall$

derived mental retardation

8/10/2019 Cong Mal


Mutant Genes

• Man$ congenital malformations areinherited – ,ome show a clear mendelian attern of

inheritance – In man$ cases anormalit$ is attriuted to a

change in the structure or function of a singlegene6 .single gene mutation

– Estimated that this t$e of defect ma(es uaout ?% of all human malformations

– 1ominant vs6 recessive vs6 -lin(ed !alsorecessive&

Date post:	02-Jun-2018
Category:	Documents
Upload:	juanitocabatanalimiii
View:	219 times
Download:	0 times

Cong Mal

Documents