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Human Birth Defect
Qian Xiaojing
Dept. of Anatomy, Histology &
Embryology
PUMC
Tel:69156461
E-mail : pumc_he@126.com
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Introduction
Causes of birth defects
Genetic factors
Environmental factors
Multifactorial inheritance
Diagnosis & treatment
Content
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I. Introduction
1.Birth defect (congenital
malformation / anomaly)
2. Teratology (dysmorphology)
“Study of monster”
Study the causes, mechanisms, and
patterns of abnormal development.
Developmental disorders present
at birth.
structural, functional, metabolic,
behavioral, or hereditary
disorders.
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3. Types of birth defects
not all variations of development are anomalies
malformation
畸形
disruption
破坏
deformation
变形
dysplasia
发育不良 • intrinsic
•abnormal from
the beginning
(primordium)
•extrinsic
breakdown
•not inherited
mechanical
forces dyshistogenesis
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4. Incidence of birth defect
• infant mortality ~20%
• major anomalies ~5%
• minor anomalies ~15%
multiple minor defects
↓
1/ more major defects
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II. Causes of Birth Defects
1. Genetic factors
2. Environmental factors
3. Multifactorial inheritance
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1. Genetic factors 1/3
• Numerical abnormalities of chromosomes
• Structural abnormalities of chromosomes
• Mutations of genes
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1) Numerical abnormalities of chromosomes
aneuploidy (非整倍体)
monoploidy
diploidy
(46.XY)
polyploidy (多倍体)
monosomy 单体
trisomy 三体
单倍体
hypodiploidy 亚二倍体
hyperdiploidy 超二倍体
triploidy 三倍体
tetraploidy 四倍体
tetrasomy
四体
euploidy (整倍体)
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(1) Polyploidy
triploidy
tetraploidy
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• triploidy (69, 3n)
intrauterine growth retardation
head-body disproportion
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Nondisjunction
(2) Aneuploid 非整倍体
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(2) Aneuploidy
Autosomes Sex
chromosomes
Monosomy lethal 1%
Trisomy √
√
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a. hypodiploid of sex chromosomes
Turner syndrome (45, X)
• short stature
• webbed neck
• defective gonadal development
• absence of sexual maturation
• mental retardation
• lymphedema
Mosiacism (45, X / 46, XX)
亚二倍体
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cystic hygroma (囊状水囊瘤)lymphangioma(淋巴管瘤 ) lymphedema
Turner syndrome
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b. hyperdiploid of sex chromosomes
XYY
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Klinefelter’s syndrome
• testicular atrophy
• sterility
• gynecomastia (男子女性型乳房)
(47, XXY; 48, XXXY; 49, XXXXY)
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mental deficiency
heart defects
c. Trisomy of autosomes
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Trisomy 21 (Down syndrome)
John Langdon Down, 1866
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• special face
flat nasal bridge
protruding tongue
upward slant to palpebral fissures
• mental retardation
• short stature
• heart defect
• transverse palmar flexion
crease
Trisomy 21 (Down syndrome)
贯通掌
睑裂上斜
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Down’s syndrome & Alzheimer Disease
• Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by
modulating glutamate receptor recycling in Down's syndrome. Nat Med, 2013.
19(4): p. 473-80.
• Sorting nexin 27 regulates Abeta production through modulating gamma-secretase
activity. Cell Rep, 2014. 9(3): p. 1023-33.
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2) Structural abnormalities of chromosomes
• Deletion
• Inversion
• Translocation
• Duplication
• Ring chromosome
• Isochromosome
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• microcephaly
• mental retardation
• developmental delay
• behavioral problems
• speech & communication
problems
• congenital heart disease
Cri du chat syndrome
5p- → catlike cry
“cry of the cat” in French
• deletion
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Angelman syndrome
(happy puppet syndrome)
maternal 15q12-
• severe mental retardation
• microcephaly
• brachycephaly 短头
• ataxic movement运动失调
• excessive laughter
Prader-Willi syndrome
paternal 15q12-
• mild mental retardation
• obesity
• hyperphagia (摄食过量)
• hypogonadism PWS AS
genetic imprinting • microdeletion
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1. Genetic factors
• Numerical abnormalities of chromosomes
• Structural abnormalities of chromosomes
• Mutations of genes
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Phenylketonuria (PKU)
3) Mutations of genes
苯丙酮尿症
mental retardation
absent of pigments
phenylalanine hydroxylase deficiency
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Achondroplasia 软骨发育不全
• short stature
• short limbs & fingers
• prominent forehead
nt1138 G>A or G>C Fibroblast growth factor receptor 3 (FGFR3)
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II. Causes of birth defects
1. Genetic factors
2. Environmental factors
3. Multifactorial inheritance
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1) Teratogens
1941, N. Gregg, rubella virus, cataracts, cardiac defects, deafness
1961, W.Lenz , thalidomide, a sedative, severe limb defect
(白内障) (风疹病毒)
(酞胺哌啶酮)
Worldwide attention on the role of drugs & viruses
as cause of human birth defects
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• Radiation
• Mechanical factors
• Environmental chemicals
• Infectious agents
• Maternal factors
• Drugs
1) Teratogens
A teratogen is any agent that can produce a congenital
anomaly or raise the incidence of an anomaly in the
population.
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atomic explosion over Japan
Survived pregnant women:
28% aborted;
25% died <1 year;
25% severe birth defect (CNS)
•ultrasonic waves
(1) Radiation
• acute high does
• diagnostic radiation
cell death, chromosome injury,
mental deficiency,
deficient physical growth
no confirmed harmful effects
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• Oligohydramnios
• Amniotic bands
(2) Mechanical factors
Congenital hip dislocation先天性髋关节脱位 clubfoot马蹄内翻足
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• organic mercury
Minamata disease (水俣病)
neurologic & behavioral disturbance
(3) Environmental Chemicals
• lead, polychlorinated biphenyls… (聚氯联二苯)
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• Fukishima meltdown Mar 11, 2011
congenital hypothyroidism in 5 US states
increased by 16%, compared to 2010
福岛
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(4) Infectious agents
• T: Toxoplasma Gondii (TG)
• O: other (syphilis)
• R: Rubella virus
• C: Cytomegalovirus (CMV)
• H: Herpes simple virus (HSV)
TORCH infections
cause similar clinical &
pathological manifestations
弓形虫
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fetal death
classic triad of symptoms
• diffused intracranial calcification
• chorioretinitis
• hydrocephaly
• Toxoplasma Gondii, TG
intracellular parasite
intracranial calcification chorioretinitis
弓形虫
脉络膜视网膜炎
脑积水
transplacental
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4-5w
Congenital rubella
syndrome (CRS)
cataract
deafness
cardiac defects
德国麻疹
• Rubella
German measles
风疹
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• spontaneous abortion
• Infection later in pregnancy
may result in severe birth
defects
IUGR
deafness
eye defects
microcephaly ( 小头)
cerebral palsy (脑瘫)
hepatosplenomegaly
• Cytomegalovirus (CMV)
most common viral infection of fetus
1%
肝脾肿大
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cutaneous lesion
• Herpes simplex virus (HSV) 单纯疱疹病毒
abortion,
prematurity
most often during
delivery
Skin, eyes, mouth (SEM)
*CNS disease
• Varicella
skin scarring
muscle atrophy,
hypoplasia of limbs
eye and brain damage
mental deficiency
Highly infectious
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tetracycline
bones & teeth
Antibiotics:
四环素 链霉素
Penicillin widely used during pregnancy for >30yrs
Streptomycin
deafness
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deafness,abnormal teeth & bones, mantel deficiency, facial defects
• Treponema pallidum 梅毒螺旋体
• Human immunodeficiency virus (HIV)
delivery
breast-feeding
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• nutritional deficiencies
1st trimester hypertension & strokes
2ed trimester heart disease & diabetes
3rd trimester blood clotting defects
The embryonic origin of adult-onset illnesses
Barker hypothesis
David Barker
(5) Maternal factors
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• Diabetes
spontaneous miscarriage
birth defect
• macrosomia (巨大儿)
• sirenomelia (并肢)
• brain abnormalies
• skeletal defects
• congenital heart defects
(5) Maternal factors
• Thyroid disease • cretinism
• goiter
• phenylketonuria
• brain damage
• mental deficiency cretinism
(呆小症)
sirenomelia
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FDA Pregnancy Categories
• The FDA has established five categories to indicate the potential of a drug to
cause birth defects if used during pregnancy.
• Category A: failed to demonstrate a risk to the fetus
• Category B: Animal studies: failed to demonstrate a risk to the fetus
no adequate & well-controlled studies in pregnant women.
• Category C: Animal studies: an adverse effect on the fetus
no adequate and well-controlled studies in humans
• Category D: positive evidence of human fetal risk,
potential benefits may warrant use of the drug in pregnant
women despite potential risks
• Category X: studies in animals or humans have demonstrated fetal abnormalities
use of the drug in pregnant women clearly outweigh potential benefits
(6) Drugs
absolute contraindication in pregnancy
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Tranquilizers (镇静剂): thalidomide
Antibiotics: tetracycline, streptomycin derivatives
Analgesic : (镇痛药): aspirin, acetaminophen ( 对乙酰氨基酚,扑热息痛)
Hormone: androgens, progestogens, diethylstilbestrol (DES),
Antineoplastic agents (抗肿瘤药): aminopterin (氨基蝶呤)
Retinoic acid: isotretinoin (异维甲酸)
Antihypertensive agent: inhibit angiotensin converting enzyme (ACEI)
Insulin & hypoglycemic drugs(降糖药 )
Thyroid drugs: potassium iodide, radioactive iodine
Anticoagulants (抗凝剂): warfarin (华法林)
Anticonvulsants (抗癫痫药): trimethadione (三甲双酮), phenytoin (苯妥英), valproic
acid (丙戊酸)
Psychotroic drug(治疗精神疾病药物): lithium, benzodiazepine derivatives (苯并二氮卓类 )
Social drugs: Cigarette smoking, Alcohol
Illicit drugs (违禁药): marijuana (大麻) , cocaine, methadone (美沙酮)
(6) Drugs
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• meromelia(部分缺肢畸形)
phocomelia, amelia, micrmelia
• hemangioma (血管瘤)
• absent of ears
phocomelia (短肢,海豹肢)
Thalidomide
amelia (无肢)
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V ertebral
A nal
C ardiac
T rachea
E sophageal
R enal
L imb
己烯雌酚
Hormones
anal stenosis
• diethylstilbestrol (DES):
genital tract anomalies
• Oral contraceptive
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• aminopterin (氨基蝶呤)
• methotrexate (氨甲蝶呤)
folic acid antagonist
folate-binding protein
• intrauterine death
• CNS & skeletal defect
Antineoplastic agents
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Retinoic acid 视黄酸,维甲酸
a metabolite of vitamin A
• craniofacial dysmorphism
• micortia
• micrognathia
• cleft palate
• thymic aplasia
• cardiovascular defects
• neural tube defects
Isotretinoin 异维甲酸
Dosage of vitamin A
小耳
小颌
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Cigarette
nicotine causes hypoxia
• intrauterine growth retardation (IUGR)
• premature delivery
• low birth weight
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Alcohol: fetal alcohol syndrome (FAS)
• mental deficiency
• special face
•smooth philium
• thin upper lip
(人中)
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2) Principles in teratogenesis
Critical periods of development
Dosage of the drug or chemical
Genotype ( genetic constitution) of the embryo
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(1) Highly sensitive period
3rd-8th w, embryonic period, organogenetic period
Tissue & organ are forming
cell division, differentiation, and morphogenesis are at their peak
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(2) Different organs have different susceptible period
corresponding to their own critical development stage.
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《中国出生缺陷防治报告(2012)》
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(3) Different teratogens also have different susceptible
period.
• Rubella virus
1st mon. 50%; 2nd mon. 22%; 3rd month 7%.
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• Thalidomide
Critical period for limb development: 24-36day
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3. Multifactorial inheritance
combination of genetic & environmental factors
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III. Diagnosis & treatment
1.Education
• Away from deleterious factors
• Folate supplementation
2. Prenatal Diagnosis
3. Treatment
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1) Noninvasive prenatal diagnosis
• Fetal monitoring
fetal heart rate monitoring
• Ultrasound
• Isolation of fetal cells in maternal blood
Trisomy 21
2. Prenatal Diagnosis
2) Invasive prenatal diagnosis
high-risk pregnancies
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2) Invasive prenatal
diagnosis
• Amniocentesis
(15-18W, LNMP)
• Chorionic villi sampling (CVS)
(10-12W, LNMP)
• Fetoscopy
2. Prenatal Diagnosis
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3. Treatment
• drugs
• surgery
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Summary
I. Introduction
II. Causes of birth defects
1.Genetic factors
a) Numerical abnormalities of chromosomes
b) Structural abnormalities of chromosomes
c) Mutations of genes
2.Environmental factors
3.Multifactorial inheritance
III. Diagnosis and treatment
summary
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• Radiation
• Mechanical factors
• Environmental chemicals
• Infectious agents
• Maternal factors
• Drugs
Teratogens
A teratogen is any agent that can produce a congenital
anomaly or raise the incidence of an anomaly in the
population.
summary
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Highly sensitive period
3rd-8th w, embryonic period, organogenetic period
Tissue & organ are forming
cell division, differentiation, and morphogenesis are at their peak
summary