human birth defectanatomy.sbm.pumc.edu.cn/mobile/files/pdf/histology...protruding tongue upward...

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Human Birth Defect

Qian Xiaojing

Dept. of Anatomy, Histology &

Embryology

PUMC

Tel：69156461

E-mail : [email protected]

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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


• 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


• 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


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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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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) 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


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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

human birth defectanatomy.sbm.pumc.edu.cn/mobile/files/pdf/histology...protruding tongue upward...

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