Trisomy 13- Patau syndromeTrisomy 13- Patau syndrome

Mental deficiency;Mental deficiency;

Severe central nervous system Severe central nervous system malformations; malformations;

Sloping forehead; malformed ears, scalp Sloping forehead; malformed ears, scalp defects; defects;

Microphthalmia; Microphthalmia;

Bilateral cleft lip and/or palate;Bilateral cleft lip and/or palate;

Polydactyly; posterior prominence of the Polydactyly; posterior prominence of the heels.heels.

Trisomy 18- Edwards syndromeTrisomy 18- Edwards syndrome

Mental deficiency;Mental deficiency;

growth retardation; growth retardation;

prominent occiput; short sternum; prominent occiput; short sternum; ventricular septal defect; ventricular septal defect;

micrognathia; micrognathia;

low-set malformed ears, low-set malformed ears,

flexed digits, flexed digits,

hypoplastic nails; rocker-bottom feet.hypoplastic nails; rocker-bottom feet.

Turner syndrome- XO Turner syndrome- XO

Klinefelter syndrome- XXY trisomyKlinefelter syndrome- XXY trisomy

Small testes, hyalinization of seminiferous Small testes, hyalinization of seminiferous tubules; aspermatogenesis; tubules; aspermatogenesis;

Often tall with disproportionately long Often tall with disproportionately long lower limbs. lower limbs.

Intelligence is less than in normal siblings. Intelligence is less than in normal siblings.

Approximately 40% of these males have Approximately 40% of these males have gynecomastiagynecomastia

Cri du chat syndrome- terminal Cri du chat syndrome- terminal deletion chromosome 5deletion chromosome 5

Fragile X syndromeFragile X syndrome

1 in 1500 male births 1 in 1500 male births

may account for much of the excess of may account for much of the excess of males in the mentally retarded populationmales in the mentally retarded population

Achondroplasia Achondroplasia

TERATOGENSTERATOGENS

Any agent that can produce a congenital anomaly or oncrease the Any agent that can produce a congenital anomaly or oncrease the incidence an anomaly in the populationincidence an anomaly in the population

TERATOLOGYTERATOLOGY

Study of causes, mechanisms, and Study of causes, mechanisms, and patterns of abnormal developmentpatterns of abnormal development

Basic concept is that certain stages Basic concept is that certain stages of embryonic development are more of embryonic development are more vulnerable to disruption than othersvulnerable to disruption than others

Organs and parts of embryo are most Organs and parts of embryo are most sensitive to teratogenic agents during sensitive to teratogenic agents during periods of rapid differentiationperiods of rapid differentiationPossible mechanisms of action include Possible mechanisms of action include alteration in intracellular matrix and fetal alteration in intracellular matrix and fetal environmentenvironmentTeratogens probably cause disruption of Teratogens probably cause disruption of gene activity at any critical stagegene activity at any critical stage

Principles of teratogenesisPrinciples of teratogenesis

Critical periods of developmentCritical periods of development

Dosage of drug or Dosage of drug or chemicalchemicalGenetic constitution of the embryoGenetic constitution of the embryo

DRUGS DRUGS

THALIDOMIDETHALIDOMIDE

alcoholalcohol

Phenytoin Phenytoin

Viruses Viruses

Rubella Rubella

Toxoplasma infectionToxoplasma infection

Female hormones Female hormones

Masculinisation of female external Masculinisation of female external genitalia due to maternal use of genitalia due to maternal use of

drug during pregnancydrug during pregnancy

STATISTICSSTATISTICS

50% of all human conceptions are lost 50% of all human conceptions are lost either before implantation or soon either before implantation or soon afterwardsafterwards15% of recognized pregnancies end in 15% of recognized pregnancies end in spontaneous abortion before 12 weeks spontaneous abortion before 12 weeks gestationgestation80-85% of aborted embryos have gross 80-85% of aborted embryos have gross structural abnormalities, varying from structural abnormalities, varying from complete absence of embryo in complete absence of embryo in gestational sac [blighted ovum] to a very gestational sac [blighted ovum] to a very distorted body shape, or a specified distorted body shape, or a specified abnormality in a single body systemabnormality in a single body system

STATISTICS………STATISTICS………

20-30% of all perinatal deaths occur as a 20-30% of all perinatal deaths occur as a result of a serious structural abnormalityresult of a serious structural abnormality

In 80% of these cases, genetic factors can In 80% of these cases, genetic factors can be implicated, with a recurrence rate of be implicated, with a recurrence rate of 1% or more1% or more

2-3% of all newborns have at least one 2-3% of all newborns have at least one major abnormalitymajor abnormality

10% newborns have minor abnormalities10% newborns have minor abnormalities

STATISTICS……………STATISTICS……………

Anomalies can be single or multiple, and Anomalies can be single or multiple, and of minor or major clinical significanceof minor or major clinical significance14% of newborns have single minor 14% of newborns have single minor anomaly anomaly Minor anomalies indicate presence of Minor anomalies indicate presence of associated major anomaliesassociated major anomaliesPresence of a single umbilical artery is Presence of a single umbilical artery is associated with cardiovascular or renal associated with cardiovascular or renal anomaliesanomalies90% of babies with 3 or more minor 90% of babies with 3 or more minor anomalies also have 1 or more major anomalies also have 1 or more major defectsdefects

STATISTICS………STATISTICS………

If 2 or more abnormalities are If 2 or more abnormalities are present in a newborn infant, there is present in a newborn infant, there is a 10-20% risk of a major a 10-20% risk of a major malformationmalformation25% of newborn babies with a major 25% of newborn babies with a major malformation die in early infancy-malformation die in early infancy-25% have a subsequent mental 25% have a subsequent mental physical disability-the remaining 50% physical disability-the remaining 50% have a fair to good outlook after have a fair to good outlook after treatmenttreatment

Causes of congenital anomaliesCauses of congenital anomalies

Brief historyBrief history

1941- 11941- 1stst well-documented reports of maternal well-documented reports of maternal rubella infection as a cause of cataracts, cardiac rubella infection as a cause of cataracts, cardiac defects and deafness in the offspringdefects and deafness in the offspring

Thalidomide tragedy- thalidomide was widely Thalidomide tragedy- thalidomide was widely used as a sedative during 1958-1962. Severe used as a sedative during 1958-1962. Severe limb anomalies were seen in babies born to limb anomalies were seen in babies born to mothers who took it in 1mothers who took it in 1stst trimester trimester

40% of these babies died in early infancy due to 40% of these babies died in early infancy due to severe cardiac, renal or GI anomaliessevere cardiac, renal or GI anomalies

Genetic factorsGenetic factors

50-60% of spontaneously aborted fetuses 50-60% of spontaneously aborted fetuses have chromosomal abnormalitieshave chromosomal abnormalities1/31/3rdrd of all congenital anomalies are of all congenital anomalies are caused by genetic factorscaused by genetic factorsAutosomes and/ or sex chromosomes can Autosomes and/ or sex chromosomes can be affectedbe affectedPersons with chromosome abnormalities Persons with chromosome abnormalities have characteristic have characteristic phenotype-phenotype- they they often look more like other similarly often look more like other similarly affected persons than their siblings affected persons than their siblings

Abnormal chromosome numberAbnormal chromosome number

Usually as a result of Usually as a result of non disjunctionnon disjunction of of homologous chromosomes or 2 homologous chromosomes or 2 chromatids of a chromosome in mitosis or chromatids of a chromosome in mitosis or meiosismeiosisThis results in trisomyThis results in trisomyDown syndrome is an example of trisomy Down syndrome is an example of trisomy affecting autosomesaffecting autosomesIn Klinefelter syndrome trisomy affects In Klinefelter syndrome trisomy affects sex chromosomessex chromosomes

Abnormal chromosome structureAbnormal chromosome structure

TranslocationTranslocation

DeletionDeletion

Ring chromosomeRing chromosome

A,A, Reciprocal translocation. Reciprocal translocation. B,B, Terminal deletion. Terminal deletion. C,C, Ring chromosome. Ring chromosome. D,D, Duplication. Duplication. E,E, Paracentric inversion. Paracentric inversion. F,F, Isochromosome. Isochromosome. G,G, Robertsonian Robertsonian

translocation..translocation..

Gene mutation (gene defect)Gene mutation (gene defect)

8%of all anomalies 8%of all anomalies

Loss or change in function of a geneLoss or change in function of a gene

Most mutations are deleterious and some Most mutations are deleterious and some are lethal are lethal

Environmental agents such as radiation Environmental agents such as radiation can accelerate mutation ratecan accelerate mutation rate

Anomalies due to gene mutation are Anomalies due to gene mutation are inherited as recessive or dominant traitsinherited as recessive or dominant traits

Environmental factorsEnvironmental factors

Teratogens: agents that can produce a Teratogens: agents that can produce a congenital anomaly or increase the congenital anomaly or increase the incidence of an anomalyincidence of an anomaly

Environmental factors may stimulate Environmental factors may stimulate genetic conditions when two or more genetic conditions when two or more children of normal parents are affectedchildren of normal parents are affected

Not everything that is familial is “genetic”Not everything that is familial is “genetic”