Congenital Defects and Teratology Flashcards Preview

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Flashcards in Congenital Defects and Teratology Deck (31):
1

CONGENITAL DEFECTS AND TERATOLOGY

CONGENTIAL DEFECTS:
    1. CONGENTITAL DEFECTS (BIRTH DEFECTS)- ALL STRUCTURAL AND
         FUNCTIONAL ABNORMALITIES  PRESENT BEFORE OR AT BIRTH
    2. MAY BE APPARENT AT BIRTH, E.G. MEROMELIA
    3. MAY NOT SHOW UP RIGHT AWAY, E.G. SOME OF THE HEART DEFECTS
    4. DEFECTS VARY IN SEVERITY FROM MINOR TO INCOMPATIBLE W/ LIFE
    5. IN GENERAL, THE EARLIER A PROBLEM OCCURS PRENATALLY, THE
         MORE SERIOUS IT IS.
    6. >20% OF INFANT DEATHS IN USA ARE CAUSED BY CONGENITAL DEFECTS
TERATOLOGY= STUDY OF ABNORMAL DEVELOPMENT/ CONGENITAL DEFECTS
    1. CONCERNED WITH VARIOUS GENETIC AND ENVIRONMENTAL FACTORS   THAT DISTURB NORMAL DEVELOPMENT
    2. HELPS UNDERSTAND NORMAL AND ABNORMAL DEVELOPMENT
    3. MAY ALLOW BETTER CONTROL OVER NORMAL DEVELOPMENT
    4. MAY HELP PREVENT ABNORMAL DEVELOPMENT
HISTORY OF FIELD
POLYMASTIA - MANY MAMMARY GLANDS
    1. KNOWN SINCE ANCIENT TIMES/ EGYPTIANS, PERUVIANS,  EARLY ART
    2. ORIGINALLY ASSOCIATED WITH DEVINE WILL, DEMONS, EVIL EYE;
         MOTHER OFTEN BLAMED
    3. ONLY RECENTLY REALIZED THESE ARE NOT CAUSES
    4. NOW TOPIC OF CONSIDERABLE SCIENTIFIC STUDY


 

Polymastia=many mammary glands

crytorchism=testes remain in abdominal cavity

polydactale=too many fingers

osteogenesis imperfecta (fragile bones)

cystic fibrosis-respritory/intestine problem..sticky mucus

 

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INCIDENCE OF DEFECTS IN HUMAN ORGANS

SLIDE: INCIDENCE OF DEFECTS IN HUMAN ORGANS AT BIRTH
    1. ORGANS SHOW DIFFERENT FREQUENCY OF CM
    2. BRAIN AND HEART HAVE A HIGH INCIDENCE
    3. EAR ALTHOUGH COMPLEX IN ORIGIN HAS LOW INCIDENCE
    4. SOME DEFECTS ARE NOT VISIBLE AT BIRTH BUT SHOW UP LATER
    5. SOME NEVER DIAGNOSED

PREVELANCE
    1. 3-5% SHOW 1 OR MORE AT BIRTH
    2. BY END OF 1 YEAR THIS = 5-10%
    3. THE FREQUENCY OF A PARTICULAR DEFECT VARIES GEOGRAPHICALLY
        A. ANECEPHALY IN 0.4% OF BIRTHS IN NORTHERN IRELAND BUT
            ONLY 0.05% 9N WEST AFRICA
    4. GIVEN COMPLEXITY OF DEVELOPMENT, AMAZING ANYONE IS NORMAL

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FACTORS EFFECTING OCCURRENCE OF CONGENTIAL DEFECTS

1. GENETIC
    A. CHROMOSOMAL ABNORMALITIES - MAY BE NUMERICAL OR   STRUCTURL
    B. MUTANT GENES
    C. ONLY RECOGNIZED RECENTLY (1940S)
2. ENVIRONMENTAL FACTORS
    A. RUBELLA FIRST ENV FACTOR RECOGNIZED
    B. INTRAUTERINE INJURY CAUSED BY DRUGS, RADIATION,    INFECTION
3. MULTIFACTORIAL 
    A.  COMBINATION OF GENETIC AND ENVIRONMENTAL FACTORS   

 

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CHROMOSOMAL ABNORMALITIES CAN BE EITHER NUMERICAL OR STRUCTURAL 

TRIPLOIDY = EXAMPLE OF POLYPLOIDY = NUMERICAL PROBLEM

 

CHROMOSOMAL ABORMALITIES/ KARYOTYPE - USED TO STUDY
    1. MAY BE NUMERICAL OR STRUCTURAL
    2. NORMAL COMPLEMENT= 46 XX OR 46 XY
NUMERICAL/MOST IMPORTANT
1. POLYPLOIDY
    A. CELLS HAVE MULTIPLES OF THE HAPLOID # OF CHROMOSOMES
    B. TRIPLOIDY= TRIOS OF EACH CHROMOS.= 69XXX
        1. MOST COMMON TYPE OF POLYPLOIDY IN HUMANS
        2. DISPERMY COULD CAUSE IT OR FAILURE OF EGG TO CAST OFF 2ND PB
        3. MAY DEVELOP OK 1ST 1/2 OF TERM THEN SICKEN AND DIE
        4. A FEW HAVE BEEN BORN (PROB MOSAICS) BUT DIES SOON  AFTER BIRTH
2. HAPLOIDY
    A. 1/2 NORMAL # CHROMOSOMES
    B. CAUSED BY PARTHENOGENESIS OR GYNOGENESIS (SPERM
         ACTIVATES EGG BUT PLAYS NO FURTHER ROLE).
    C. DO NOT DEVELOP BEYOND MID TERM
3. ANEUPLOIDY: A DEVIATION FROM THE DIPLOID # ( E.G.45=HYPODIPLOID)
    A. MONOSOMY= ONE CHROMOSOME MISSING
        1. MONOSOMY OF AUTOSOME CAUSES DEATH
        2. MONOSOMY OF SEX CHROMOSOME- MANY DIE BUT SOME SURVIVE=
            TURNERS (XO) SYNDROME.
A. USUALLY CAUSED BY NONDISJUNCTION IN   THE MALE.
B.  CHARACTERISTICS= WEBBED NECK, SWOLLEN HANDS,SHORT
              STATURE, ABSENCE OF OVARIES, MENTAL RETARDATION

 

 

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ANEUPLOIDY – another type of numerical defect – one too many or one too few chromosomes

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Embryotoxic vs teratogenic

embryotoxic-kills embryo

teratogenic-congenital defect, not death

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STRUCTURAL CHROMOSOMAL ABNORMALITIES

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TRANSLOCATIONS
DELETIONS
DUPLICATIONS
INVERSION
ISOCHROMOSOME

STRUCTURAL ABNORMALITIES/STUDY INFO IN MOORE
1. INCLUDES TRANSLOCATIONS, DELETIONS, DUPLICATION, INVERSION, OR
    ISOCHROMOSOME (CENTROMERE DIVIDES TRANSVERSELY NOT
       LONGITUDINALLY)

NEXT SLIDE SHOWS AN EXAMPLE OF A DELETION

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CRI DU CHAT – example of a deletion

CRI DU CHAT SYNDROME
        1. CAUSED BY A PARTIAL TERMINAL DELETION FROM THE SHORT
             ARM END OF CHROMOSOME #5.
        2. ALL AFFLICTED INDIVIDUALS HAVE SEVERE MENTAL RETARDATION
        3. MAY ALSO HAVE CONGENITAL HEART DISEASE AND A WEAK CAT
             LIKE CRY

Rare about 1:50,000

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ANGELMAN SYNDROME AND PRADER-WILLI SYNDROME

MICRODELETION ON CHROMOSOME #15

ANGELMAN
DEFECTIVE ALLELE ON #15 IS FROM MOTHER
MENTALLY RETARDED, CAN NOT SPEAK, POOR MOTOR DEVELOPMENT, INAPPROPRIATE LAUGHTER

PRADER-WILLI
DEFECTIVE ALLELE ON #15 IS FROM FATHER
OBESITY, MENTALLY RETARDED, HYPOGONADISM, CRYTORCHISIM

TWO INTERESTING DISTINCT   MENTAL RETARDATION SYNDROMES

BOTH CAUSED BY THE SAME THING - MICRODELETION ON CHR #15

PHENOTYPES ARE VERY DIFFERENT - SEE PICTURES IN TEXT

ANGELMANS - DEFECTIVE #15 COMES FROM MOTHER
PRADER-WILLI - DEFECTIVE #15 COMES FROM FATHER
THE CRITICAL REGIONS FOR BOTH AS AND PWS ARE WITHIN THE 15Q REGION OF    CHROMOSOME #15.
BUT THE CRITICAL REGIONS ARE SEPARATE WITHIN Q15

DEFECTIVE GENE IS AN IMPRINTED ONE - SO PHENOTYPE VARIES WITH SOURCE OF DEFECTIVE GENE  (REVIEW IMPRINTING FROM EARLIER LECTURE)

NOTE: BOTH MALES AND FEMALES CAN INHERIT BOTH SYNDROMES

ANGELMAN’S: MENTAL RETARDATION, ABSENT SPEECH, SEIZURES, INAPPROPRIATE LAUGHTER, PECULIAR GAIT

PRADER-WILLI: MENTAL RETARDATION, HYPOGONADISM, HYPOTONIA, OBESITY

SYNDROMES CAN BE DETECTED BY FISH

 

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MUTANT GENES CAN CAUSE ANOMALIES

SINGLE GENE DEFECTS
MUTANT GENES
    1. SOME DEFECTS (ABOUT 8%) ARE CAUSED BY MUTANT GENES
    2. USUALLY INVOLVES LOSS OR CHANGE IN FUNCTION OF A GENE
    3. MOST MUTATIONS ARE HARMFUL
    4. ARE INHERITED IN MENDELIAN MANNER
    5. SOME EXAMPLES FOLLOW

AUTOSOMAL DOMINANT INHERITANCE
    1. CAUSES DEFECT WHETHER HETEROZYGOUS OR HOMOZYGOUS
    2. POLYDACTYLY, LOBSTER CLAW
    3. ACHONDROPLASIA: MOST COMMON SKELETL DEFECT (1/15,000) - NORMAL IQ
A. 80-90% ARE NEW MUTATIONS - OCCURS IN ALLETHNIC GROUPS - HAS COMPLETE     PENETRANCE
B. MAY BE ASSOCIATED WITH ADVANCED PATERNAL AGE
C. CAUSED BY A MUTATION IN FGF RECEPTOR3  - CAUSES DEFECT IN MATURATION OF    CHONDROCYTES IN CARTILAGE GROWTH PLATE
    4. OSTEOGENESIS IMPERFECTA: FRAGILE BONES WHICH FRACTURE PRENATALLY

AUTOSOMAL RECESSIVE
    1. RECESSIVE GENE EXPRESSES ITSELF ONLY WHEN HOMOZYGOUS INHERITED FROM BOTH   PARENTS
    2. RARE /MANY CARRIERS REMAIN UNDETECTED
    3. E.G. MICROCEPHALY, CONGENITAL ADRENAL HYPERPLASIA

SEX LINKED INHERITANCE
    1. ABNORMAL GENES CARRIED ON X CHROMOSOME
    2. SEX LINKED DOMINATE NOT SHOWN FOR HUMAN
    3. RECESSIVE WOULD BE SHOWN IN XY BUT NOT XX/ ABOUT 300 FOR HUMANS
    4. TRANSMITTED FROM MOTHER TO SONS/ IN 1/2 SONS
    5. E.G., SLIDES: HYDROCEPHALUS (XS CSF), HEMOPHILIA

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MUTANT GENES:
AUTOSOMAL RECESSIVE INHERITANCE

RECESSIVE MUTATION

AUTOSOMAL RECESSIVE
    1. RECESSIVE GENE EXPRESSES ITSELF ONLY WHEN HOMOZYGOUS-  INHERITED FROM  BOTH PARENTS
    2. RARE /MANY CARRIERS REMAIN UNDETECTED
    3. CYSTIC FIBROUS IS CAUSED BY A RECESSIVE MUTATION
A. ABOUT 1 IN 23 PEOPLE IN US CARRY AT LAST ONE DEFECTIVE GENE
B. MOST COMMON GENETIC DEFECT OF ITS SEVERITY IN US
C. PEOPLE W/ CF HAVE CRONIC LUNG INECTIONS AND DIGESTIVE DISORDERS
D. LIFE EXPECTANCY NOW ABOUT 30 YEARS (USED TO BE 8 YEARS)
E. CAUSED BY DEFECT IN GENE PRODUCIN G PROTEIN CALLED CFTR
  1. CONTROLS FLOW OF CHLORIDE ACROSS CELL MEMBRANE
    3. OTHER DEFECTS THAT MAY BE INHERITED AS RECESSIVE MUTATIONS ARE.    MICROCEPHALY, CONGENITAL ADRENAL HYPERPLASIA

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MUTANT GENES: SEX-LINKED INHERITANCE

SEX LINKED INHERITANCE
    1. ABNORMAL GENES CARRIED ON X CHROMOSOME
    2. SEX LINKED DOMINATE NOT SHOWN FOR HUMAN
    3. RECESSIVE WOULD BE SHOWN IN XY BUT NOT XX/ ABOUT 300 FOR HUMANS
    4. TRANSMITTED FROM MOTHER TO SONS/ IN 1/2 SONS
    5. E.G., SLIDES: HYDROCEPHALUS (XS CSF), HEMOPHILIA

FRAGILE X SYNDROME
A. MOST FREQUENTLY INHERITED CAUSE OF MENTAL RETARDATION AFTER DOWNS SYNDROME
1. CAUSES 10% OF ALL CASES OF MENTAL RETARDATION
2. USUALLY FOUND IN MALES, BUT ALSO OCCURS IN FEMALES
B. JAW PROMINENT, EARS LARGE, FACE LONG AND NARROW BUT NOTICE HOW NORMAL THEY  LOOK

C. A GENE (FMR-1 - FRAGILE X MENTAL RETARDATION GENE) ON LONG ARM OF X CHROMOSOME  CAUSES AN UNSTABILE FRAGILE SITE  IN CHROMOSOME
A. IF IN FMR1 GENE THERE ARE CGG REPEATS - IF FEWER THAN 40 REPEATS - NO    PROBLEM
B. IF 55-200 REPEATS INDIVIDUAL HAS PREMUTATION STATE
C. MALES WITH MORE THAN 200 REPEAT HAVE SYNDROME
D. FEMALES WITH > 200 REPEATS HAVE ABOUT 50% OF HAVING LOW OR BORDERLINE IQ
  1. FEMALES WITH >200 REPEATS W/ NORMAL IQ MAY HAVE LEARNING PROBLEMS
E. WHEN MORE THAN 200 REPEATS,GENE BECOMES METHYLATED - TURNED OFF
F. NO FMR1 PROTEIN IS MADE - CAUSES COGNITIVE FEATURES AND CONNECTIVE TISSUE   PROBLEMS OF FRAGILE  X

SIBS AT TOP. SISTER HAS MILD LEARNING DISABLITY - BOTH  X CHROMOSOMES AFFECTED
 

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C-KIT MUTATIONS/heterozygous mutation

MUTATIONS MAY AFFECT PHENOTYPE MILDLY WHEN HETEROZYGOUS
KIT MUTATION ON ONE ALLELE

HETEROZYGOUS FOR KIT

KIT IS NEED FOR CELL MIGRATIONS - E G., PGC, BLOOD CELLS, MELANOCYTES AND NCC

BOTH MOUSE AND BABY ARE HETEROZYGOUS - MAKE 1/2  NORMAL AMOUNT OF KIT GENE PRODUCT - NOT ENOUGH KIT GENE PRODUCT IS MADE FOR NORMAL MIGRATION OF ALL PIGMENT CELLS

NOTE THEIR PIGMENTATION IS AFFECTED

DEFECT IN KIT LIGAND (BINDS TO KIT) ON SURFACE OF CELLS ON MIGRATORY PATHWAY CAUSES SAME EFFECT

 

C-Kit heterozygous-->different color pattern

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ENVIRONMENTAL FACTORS

INTRAUTERINE ENVIRONMENT
MECHANICAL DAMAGE
TERATOGENS

1. INTRAUTERINE ENVIRONMENT
    A. STRESS ON MOTHER MAY LEAD TO FETAL DEATH OR DEFECTS
    B. STRESSES= UNDERNUTRITION, OVERFEEDING, VITAMIN DEFICIENCY, HOT   CLIMATES
    C. EMOTIONAL STRESS
        1. NO NERVES IN PLACENTA
        2. CHEMICALS IN A STRESSED MOTHER MAY BE TRANSMITTED TO FETUS

2. MECHANICAL DAMAGE
    A. FETUS WELL PROTECTED BY UTERINE WALLS AND AMNIOTIC  FLUID
    B. SEVERE BLOWS OR FALLS MAY LEAD TO ABORTION/ USUSALLY
        CAUSED BY HEMMORRAGE OF PLACENTA
    C. AMNIOTIC BAND SYNDROME, OLLIGOHYDRAMNIOS

3. TERATOGENIC AGENT
    A. ANY AGENT THAT CAN INDUCE OR INCREASE THE INCIDENCE OF
         CONGENITAL  DEFECTS
          1. CAUSE 7% OF CONGENITAL MALFORMATIONS
       1.  A TERATOGEN WILL PRODUCE A SPECIFIC EFFECT FOR A GIVEN
          SPECIES WHEN APPLIED AT A SPECIFIC TIME AND DOSE

 

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What is a teratogen?

Any agent that can produce a congenital anomaly or increase the incidence of an anomaly in the population.
Infectious agents
Drugs
Chemicals
Physical Agents

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CRITICAL PERIODS OF DEVELOPMENT

1. PRENATAL DEVELOPMENT MAY BE HAZARDOUS TO YOUR HEALTH
    2. THE CHANCES OF DEATH ARE GREATER BEFORE BIRTH THAN AT ANY
        OTHER TIME EXCEPT OLD AGE
    3. SOME EMBRYOS FAIL TO IMPLANT/DIE/RESORBED
    4. SOME LOST POST IMPLANTATIONS/STILLBIRTHS/ABORTIONS
    5. PROBABLY 50-90% OF THE EGGS WHICH GET FERTILIZED DO NOT
        MAKE IT TO TERM
    6. THOSE WHICH DO MAKE IT THRU ARE NOT ALWAYS OK

THIS FIGURE SHOWS WHEN IN PRENATAL DEVELOPMENT ORGAN SYSTEMS ARE MOST SENSITIVE TO TERATOGENS

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TERATOGENS: INFECTIOUS AGENTS

CYTOMEGALOVIRUS
HERPES SIMPLEX VIRUS
HIV
HUMAN PARVOVIRUS B19
RUBELLA VIRUS
TOXOPLASMA GONDII
TREPONEMA PALLIDUM
VENZEZUELA EQUINE ENCEPHALITIS VIRUS
VARICELLA VIRUS

1. INFECTIOUS AGENTS
A. CAN CROSS THE PLACENTA AND CAUSE BIRTH DEFECTS
B. PREGNANT WOMEN SHOULD AVOID CATS (CARRY TOXOPLASMA)
D. THREE OF THE ABOVE PRODUCE HYDROCEPHALUS
2. TORCH INFECTIONS  = TOXOPLASMOSIS, OTHER (VEEV, MUMPS, COXSACKIE, PARVOVIRUS,   HIV), RUBELLA, CYTOMEGALOVIRUS, HERPES
3. CMV - HERPES FAMILY - MONO IN ADULT
A. IN FETUS -DEATH, DEAFNESS, MICROCEPHALY
4. HSV - COLD SORES, GENITAL SOREIN IN ADULT
A. IN FETUS - LEARNING AND OCULAR PROBLEMS, SKIN LESIONS
5. HIV -
A. DOES NTO CONTRIBUTE TO FETAL EMBRYOPATHY BUT TRANSMISSION RATE =   30%
5. PARVOVIRUS - FIFTH DISEASE IN ADULTS -FACIAL RASH JOINT PAIN, FLU LIKE SYMPT,  ANEMIA
A. IN FETUS - FETAL HYDROPS (FLUID ACCUMULATION),
6. . RUBELLA:  IN ADULTS CAUSESGERMAN  MEASLES
A. IN FETUS - HEART DEFECTS, CATARACTS, DEAFNESS, MENTAL RETARDATION
7. TOXOPLAMA - PARASITE -CAUSES MONOLIKE  SYMPTOMS
A. IN FETUS - SYMPTOMS LIKE THOSE OF CMV
8. TREPONEMA - IN ADULT SYPHILLIS
A. IN FETUS - HYDROCEPHALUS, DEAFNESS, MENTAL RETARDATION, ABNORMAL BONES
9. VEEV -
A. IN FETUS - MICROCEPHALY, MICROPHTHALAMIA, HYDROCEPHALY
10. VARICELLA AND HERPES ZOSTER - IN CHILDREN V CAUSES CHICKENPOX, HZ SHINGLES IN   ADULT
A. IN FETUS -MICROCEPHALY, LIMB DEFECTS, GROWTH DISTURBANCES

 

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TERATOGENS: PHYSICAL AGENTS

IONIZING RADIATION
DEATH
CNS DEFECTS
CATARACTS
CLEFT PALATE
MENTAL RETARDATION

HYPERTHERMIA
ANENCEPHALY
 

PHYSICAL AGENTS
A. MAY CAUSE DEFECTS
B.  X-RAYS: HIGH LEVELS MAY CAUSE DEATH, MICROCEPHALY,     MENTAL RETARDATION OR SKELETAL ABORMALITIES
C. HYPERTHERMIA:
HYPERTHERMIA
A. COULD BE CAUSED BY INFECTION - FEVER OR BY SAUNA BATHS
B. HAS BEEN LINKED TO ANENCEPHALY

 

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TERATOGENS: CHEMICALS

METHYL MERCURY
PCBs (polychlorinated biphenyls)

THESE ARE PRESENT IN THE ENVIRONMENT
METHYL MERCURY MAY CAUSE CEREBRAL ATROPHY,   SEIZURES, MENT RETARD
as loss of IQ points, and decreased performance in tests of language skills, memory function and attention deficits.

2. PCBs MAY CAUSE INTRAUTERINE GROWTH RETARDATION,  SKIN DISCOLORATION
 

 

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TERATOGENS: DRUGS

ALCOHOL
ANDROGENS
AMINOPTERIN
BUSULFAN
COCAINE
DES
RETINOIC ACID

LITHIUM CAROBONATE
METHOTREXATE
PHENYTOIN
TETRACYCLINE
THALIDOMIDE
VALPROIC ACID
WARFARIN

1. CHEMICAL AGENTS
A. ALL DRUGS ON THIS LIST ARE TERATOGENS
B. 18 KNOWN, THALIDOMIDE, ETOH (SLIDE), VALPROIC ACID (NTD),     COCAINE (GASTROSCHISIS)
2. HORMONES
A. ANDROGENIC AGENTS, DIETHYSTEBESTEROL (DES)
B. CAN MASCULINIZE FEMALE FETUSES AND PRODUCE AMBIGUOUS   EXTERNAL GENITALIA
C. DES LINKED TO CERVICAL CANCER IN FEMALES WHOSE MOTHER   TOOK IT WHILE PREGNANT - SHOWS UP 20 LATER; ALSO    LINKED TO REPRODUCTIVE ABNORMALITIES IN MALES
3. THOUSANDS OF CHEMICALS ETC ARE POTENTIALLY TERATOGENS BUT   VERY FEW ACTUALLY SHOWN TO BE TERATOGENS
4. CHECK TEXT AND TABLE 8-5 IN MOORE TO SEE WHAT THESE ALL DO
5. NEVER PRESCRIBE THEM FOR A PREGNANT WOMAN

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FETAL ALCOHOL SYNDROME

A. ETOH ACTS AS A TERATOGEN  DURING 1ST MONTH OF PREGNANCY
B. FAS SYNDROME MAY AFFECT EMBRYOS OF ALCOHOLIC WOMEN (40%)
C. MILD CASES (FETAL ALCOHOL EFFECTS -FAE) MAY AFFECT EMBRYOS OF   WOMEN DRINKING 2-4 OZ OF  ETOH/DAY
  1. MAY OCCUR FROM A SINGLE BOUT OF BINGE DRINKING
D. FIRST REPORTED IN FRANCE IN 1960; IN ENGLISH LIT IN 1973
E. FAS IS PROBABLY MOST COMMON CAUSE OF MENTAL RETARDATION
(NON-CHROMOSOMAL)
E. SYMPTOMS OF FAS
  1. GROWTH RETARDATION
  2. MENTAL RETARDATION/LEARNING DISABILITES
  3. FACIAL DEFECTS
  4. MAY BE MILD OR VERY SEVERE
F. SLIDE: CUTE BABY ALMOST  NORMAL - FACIAL CHARACTERS OF FAS
  1. SMALL EYE OPENINGS
  2. SMALL MAXILLA
  3. SMOOTH PHILTRUM BUT LONG PHILTRUM
  4. THIN UPPER LIP
G. FAS OCCURS ABOUT 2/1000 LIVE BIRTHS
H. COULD BE ELIMINATED IF PREGNANT WOMEN DID NOT DRINK
I. ETOH CAUSES: ABNORMAL MIGRATION OF NCC AND DEVELOPING NEURONS
1. ABSENCE OF NCC IN FRONTONASAL PROMINENCE CAN LAD TO     MIDFACIAL ABNORMLITES

 

The following characteristics are commonly found in children with FAS:
In infancy, low birth weight, irritability, feeding difficulties, sleep disturbances, alcohol withdrawal, strong startle reflex
Growth deficiencies
Small head
Vision problems
Dental abnormalities
Hearing problems
Craniofacial abnormalities - narrow eye slits, flat midface, low nasal ridge, loss of groove between nose and upper lip, small jaw
Mental retardation, developmental delays
Learning disabilities
Neurological dysfunction - attention deficit, memory deficit, hyperactivity, difficulty with abstract concepts, poor problem solving skills and judgment, difficulty learning from consequences
Epilepsy
Behavioral problems - mood swings, defensive and stubborn, lack of self-discipline, genuine innocence, detached attitude
Organ and body dysfunction - muscle problems, bone and joint problems, genital defects, heart defects, kidney defects

 

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FETAL ALCOHOL SYNDROME EXAMPLES

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FAS in Different Ethnicities

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HOLOPROSENCEPHALY

MORE SEVERE EFFECTS OF ETOH CONSUMPTION DURING  PREGNANCY
HOLOPROSENCEPHALY:
A. INDUCTION OF FOREBRAIN IS DISTURBED
B. LEADS TO SPECTRUM OF ANOMALIES = HOLOPROSENCEPHALY
C. AFFECTS DERIVATIVES OF FRONTONASAL PROCESS, CALVARIA, MIDFACIAL STRUCTURES
D. MOST CASES OF HOLOPROS ARE \CAUSED BY ETOH CONSUMPTION WHEN FOREBRAIN   INDUCTION OCCURS
E. WOMEN SHOULD NOT DRINK ETOH DURING FIRST MONTH OF PREGNANCY - EFFECTS ARE   LESS SEVERE AFTER THIS TIME
MORE SEVERE CASES OF HOLOPROSENCEPHALY CAUSED BY ETOH
1. MISSING PHILTRUM
2. SINGLE NOSTRIL
3. NO NOSE - MIDFACIAL  FEATURES DEPRESSED
4. CYCLOPIA - DEFECT IN FRONTONASAL PROMINENCE
MECHANISM OF ACTION - NOT WELL UNDERSTOOD
1. ETOH MAY DESTROY SOME CELLS IN DEVELOPING CNS AND INHIBIT FORMATION OF THE   FOREBRAIN- M RETARD
3. ALSO INHIBITS MIGRATION OF NCC
  A. NCC IMPRT IN BUILDING UP FACE - FRONTONASAL PROMIN
  B. DEFICIENCIES IN FNP CAUSE FACIAL DEFECTS
  J. MAY OCCUR IN 2/1000 BIRTHS , BUT MAY BE HIGHER
K. COULD BE PREVENTED BY NOT DRINKING DURING  1SY MONTH
G. OTHER CAUSES OF HOLOPROSENCEPHALY
A. INHALTION OF TOLUENE DURING PREGNANCY
B. DIABETIC WOMEN ARE AT HIGHER RISK
C. TRISOMIES 13,18 AND 21
D. SINGLE GENE  MUTATIONS- MURINE KO OF SHH PRODUCES PHENOTYPE LIKE HUMAN HPE

 

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ACCUTANE

VITAMIN A ANALOGUE

SPONTANEOUS ABORTION
MICROGNATHIA
MICROTIA
CARDIAC DFFECTS
NEURAL TUBE DEFECTS
CLEFT PALATE
 

ACCUTANE: = 13-CIS-RETINOIC ACID
A. A PRESCIPTION MEDICATION USED TO TREAT ACNE
B. A SYNTHETIC DERIVATIVE OF VITAMIN A
C.  APPROVED BY FDA IN 1982
D. HIGH PROBABLY OF BIRTH DEFECTS IF TAKEN DURING PREGNANCY
E. DEFECTS INCLUDE:
1. HYDROCEPHALY
2. MICROCEPHALY
3. MENTAL RETARDATION
4. SMALL/MALFROMED EARS
5. FACIAL ABNORMALITIES
6. HEART DEFECTS
7. OPEN NTD - SPINA BIFIDA CYTSICA
8. MISCARRIAGE
F. TEGISON IS A RELATED DRUG- VITAMIN A  RELATED
1. USED TO TREAT PSORIASIS
2. MAY CAUSE DEFECTS
G. FOODS LIKE TOMATOES, CARROTS YELLOW VEGGIES?
1. OK TO EAT WHILE PREGNANT
2. CONTAIN B-CAROTENE - PRECURSOR OF VIT A
3. BODY MAKES JUST ENOUGH VIT A - SO THESE ARE NOT DANGEROUS
4. BUT SHOULD NOT TAKE TOO MUCH VIT A SUPPLEMENT WHILE     PREGNANT

 

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FETAL SMOKING SYNDROME

FETAL SMOKING SYNDROME
1. SMOKERS EXPOSE FETUS TO MS AND ETS
2. SMOKE CONMPONENTS CROSS PALCENTA
3. RETARD GROWTH - LOWER BIRTH WEIGHT BABIES FOR MOTHERS WHO  SMOKE
4. ALSO SMOKING HAS BEEN LINKED TO INFERTILITY, ECTOPIC PREGANCY,   ABRUPTIO  PLACENTA, SIDS, POST NATAL LEARNING DISABILITES
5. SLIDE SHOWS A CRYSTAL OF NICOTINE

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OTHER TERATOGENS??

A. CAN BE HARD TO ESTABLISH IF A COMPOUND IS A TERATOGEN
B. THERE IS A RARE CM CALLED GASTROSCHISIS - SPLIT OPEN STOMACH
C. VENTRAL BODY WALL THIN AND TEARS - INTESTINE COME OUT
D. IT IS INCREASING - WHY?
1. EVIDENCE THAT IT MAY BE PROVOKED BY COCAINE
2. ALSO BY PSEUDOEPHRINE - OVER THE COUNTER DECONGENSTANT

5. SOME GOOD NEWS!!
A. NEURAL TUBE DEFECTS
  1. NEURULATION DOES NOT OCCUR PROPERLY
  2. SLIDE: SEM SHOWING YOUNG EMBRYO W/ ANENCEPHALY
  3. SLIDE: ANENCEPHALY AND RACHISCHISIS
  4. SLIDE: A FORM OF SPINA BIFIDA
  5. MAY BE CAUSED BY GENETIC FACTORS OR BY SOME ERATOGENS     (ACCUTANE)
B. CAN BE PREVENTED IN SIGNIFICANT # OF CASES IF WOMAN TAKES    FOLIC ACID BEFORE CONCEPTION
  1. 400 MG/DAY
  2. THIS AMOUNT IS FOUND IN CENTRUM!!

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FACTORS AFFECTING TERATOGENS

SYNERGISM AND POTENTIATION
ROUTE
DOSE
GENDER

SYNERGISM/POTENTIATION
1. A COMBO OF DRUGS MAY PRODUCE A TERATOGENIC AFFECT WHERE   NEITHER ALONE IS  HARMFUL
2. RATS: CYCLOPHOSPHATE   =20% MALFORMATIONS  5-FLUOROURACIL  10MG/KG   = 10%  MALFORMATIONS TOGETHER= 100% MALFORMATIONS
ROUTES
1. ROUTE OF DELIVERY CAN AFFECT TERATOGENICITY
2. THALIDOMIDE/ ACTIVE WHEN GIVEN ORALLY BUT NOT WHEN GIVEN   IP

DOSE DEPENDENCY
1. TERATOGEN SHOULD SHOW DOSE DEPENDENT RESPONSE/NO EFFECT  LEVEL
2. SHOULD PRODUCE CONGENITAL DEFECT NOT JUST BE EMBRYO LETHAL
3. DOSE WHICH CAUSES HARM TO EMBRYO MAY HAVE NO EFFECT ON MOTHER; DEVELOPING          SYSTEMS ARE MOST SENSITIVE TO  CHEMICALS 4.SOME TERATOGENS SHOW A PLATEAU  EFFECT
5. IN GENERAL ACUTE DOSES ARE MORE HARMFUL THAN CHRONIC DOSES
6. THALIDOMIDE WAS EFFECTIVE AS A SINGLE DOSEGENDER EFFECTS
1. FEMALES HAVE HIGHER FREQUENCY OF ANENCEPHALY, SPINA   BIFIDA, CLEFT PALATE
2. MALES HAVE HIGHER FREQUENCY OF HYDROCEPHALUS, CLEFT LIP, OMPHALOCOELE,   POLY/SYNDACTYLY
3. TOTAL MALFORMATION RATE IS HIGHER IN MALES, BUT FEMALES  HAVE HIGHER RATE OF  MULITPLE MALFORMATIONS OTHER EFFECTS
1. IN ADDITION TO EFFECTING EMBRYO DIRECTLY, CHEMICALS COULD  ACT ON MOTHER TO  AFFECT REPRODUCTION
     A. MATING, FERTILITY, OVULATION ETC
2. MALES EXPOSED TO CHEMICALS MAY AFFECT  OFFSPRING
    A. MALES EXPOSED TO ANESTHETICS OR VINYL CHLORIDE, BUT
         WIVES NOT EXPOSED, HAVE INCREASED SPONTANEOUS     ABORTIONS
    B. SOME EVIDENCE THAT MALE SMOKERS MAY AFFECT FETUS

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Better Identification of Teratogens Needed

Prenatal period is more sensitive to environmental chemicals than any other time in life cycle

Thousands of new chemicals are released every year, most without much testing

Need better ways to identify
teratogens before they are released

Faroe Island Policy Paper
 

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Stem Cells Could Be used to Identify Teratogens

Embryonic stem cells could be valuable in testing toxicity of environmental chemicals and drugs

ESC would model pre and post-implanting embryos

Development of assays with human ESC could provide a huge breakthrough in preventing congenital anomalies and human disease.

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THIS IS A GOOD TIME TO REVIEW THE METHODS TO STUDY CHROMOSOMES

LEFT = FISH - FLUORESCENCE IN SITU HYDRIDIZTION
FLUORESCENT PROBE TO CHROMOSOME 21 USED TO LABEL
FAR LEFT IS NORMAL KARYOTYPE = 2 COPIES OF 21
MIDDLE FIGURE SHOWS INDIVIDUAL WITH DOWN’S
3 COPIES OF #21

RIGHT SHOWS CHROMOSOMAL PAINTING
DIFFERENT FLUORECHROMES SPECIFIC FOR EACH PAIR  OF CHROMOSOMES IS USED TO PAINT CHROMOSOMES

CAN EASILY IDENTIFY TRISOMIES, MONOSOMIES OR   TRANSLOCATIONS 

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