10.1 congenital anomalies; pediatric pathology

Pediatric Pathology
Pediatric Pathology
Topics
Topics

Dr. Krishna Tadepalli, MD, www.mletips.com

Table 10-1. Cause of Death Related with Age
Causes*
UNDER 1 YEAR

Rate†
685.2

Congenital malformations, deformations, and chromosomal anomalies
Disorders related to short gestation and low birth weight
Sudden infant death syndrome (SIDS)
Newborn affected by maternal complications of pregnancy
Newborn affected by complications of placenta, cord, and membranes
Respiratory distress of newborn
Accidents (unintentional injuries)
Bacterial sepsis of newborn
Intrauterine hypoxia and birth asphyxia
Diseases of the circulatory system
1-4 YEARS

29.9

Accidents and adverse effects
Congenital malformations, deformations, and chromosomal abnormalities
Malignant neoplasms
Homicide and legal intervention
Diseases of the heart‡
Influenza and pneumonia
5-14 YEARS

16.8

Malignant neoplasms
Homicide and legal intervention
Congenital malformations, deformations, and chromosomal abnormalities
Suicide
Diseases of the heart
15-24 YEARS

80.1

Homicide
Suicide
Malignant neoplasms
Diseases of the heart


1. Congenital Anomalies
1. Congenital Anomalies


Congenital Anomalies
•

Leading cause of death in the first 12 months of life

• Definitions (Errors of Morphogenesis)
1. Malformations = Primary, Intrinsically abnormal developmental process,
Multifactorial (polygenic), affect single or multi-systems Ex:- Congenital heart
diseases, Anencephaly
2. Disruptions = Secondary destructions of previously normal organs, arise from
extrinsic disturbance in morphogenesis, Ex:- Rupture of amnion  Amniotic bands
 encircle/compress/attach to fetal parts (Will they repeat in next pregnancy or
not?)
3. Deformations = also an extrinsic disturbance in morphogenesis, mainly due to
compression (localized/generalized) of fetus by biochemical forces, MC underlying
factor = uterine constraint (fetal growth outpaces uterine size (during 35th -38th
wks.) Factors  Maternal (Primi, small or abnormal uterus, fibroids etc.,) or
Fetal/Placental (oligohydromnios, multiple fetuses etc.,), Ex:- Clubfeet
4. Sequence = also an extrinsic disturbance, cascade of events triggered by one
abnormality, usually single, oligohydromnios (due to maternal or fetal causes)
fetal compression  abnormalities of hands and feet (hip dislocation, Lung
Hypoplasia etc.,)
5. Syndrome = constellation of congenital anomalies can’t be explained by a single
event (unlike sequence)

Malformations
Malformations


Disruptions
Disruptions


Sequence
Sequence


Potter Sequence
Potter Sequence


Syndrome (what is it?)
Syndrome (what is it?)


• Others
6. Agenesis= Complete absence of the organ and its primordium
7. Aplasia = also like agenesis (absence of the organ) but due to failure of primordial
development
8. Atresia = absence of opening of hollow visceral organ (Trachea, Duodenum)
9. Hypoplasia = Incomplete development or decrease in size of organ with decrease in
# of cells
10. Dysplasia = abnormal or disorganization of cells


•
•
•
•

Causes of Anomalies
MCC – unknown ( in half of cases)
Among the known causes
Genetical

•

Karyotypic abnormalities;- most are defects in Gametogenesis (not familial);
most of Aneuploidy (80-90%) causes fetal deaths; (Down’s is MC)
Mendelian disorders ;- Most are AD or AR (90%); most are loss of function
mutations; Ex;- defects in hedgehog signaling pathway  Holoprosencephaly (MC
developmental defect of forebrain and mid -face) and sometimes due to gain of
function mutations (Ex;-Achondroplasia ( MC form of short limb dwarfism) 
FGFR3) gene mutations

•

• Environmental
•
•

Viruses ;- cause malformations (Rubella, CMV, HSV, HIV etc.,); at risk period
varies ( rubella = just before conception to 6th wk.); CMV = MC fetal viral infection,
asymptomatic, maximum risk is in 2nd trimester,
Drugs & Chemicals ;- table 10.2 (next slide)

• Multifactorial = due to multiple genetic polymorphism  susceptibility

phenotype + environment, Ex;- dislocation of hip ( breech presentation), cleft lip or
palate ( see table 10.3)

Table 10-2. Causes of Congenital Anomalies in Humans
Table 10-2. Causes of Congenital Anomalies in Humans
Cause

Frequency (%)

GENETIC
Chromosomal aberrations

10-15

Mendelian inheritance

2-10

ENVIRONMENTAL
Maternal/placental infections

2-3

Rubella
Toxoplasmosis
Syphilis
Cytomegalovirus
Human immunodeficiency virus
Maternal disease states

6-8

Diabetes  fetal hyper- insulinemia  Macrosomia  cardiac and neural tube anomalies (Diabetic embropathy)
Phenylketonuria
Endocrinopathies
Drugs and chemicals

1

Alcohol ;- MC teratogen; Fetal alcohol syndrome ( MR, ASD, Microcephaly, short palpebral fissures, maxillary Hypoplasia); disrupts retinoic acid and hedgehog
pathways;
Folic acid antagonists
Androgens
Phenytoin
Thalidomide (limb abnormalities = seal limbs); mechanism = up regulation of WNT repressors  down regulation of wingless WNT pathway
Warfarin
13-cis-retinoic acid
Others
Irradiations;- mutagenic, carcinogenic, teratogenic, can cause Microcephaly, spina bifida, blindness,
MULTIFACTORIAL

20-25

UNKNOWN

40-60

Drugs (Phacomelia= ? drug)
Drugs (Phacomelia= ? drug)


Dilantin
Dilantin


Spina bifida – neural tube defect ? drug
Spina bifida – neural tube defect ? drug


• Pathogenesis of Anomalies
1. Timing of prenatal teratogenic insult
– Embryonic period = 3 to 9 weeks  extremely susceptible to teratogenesis
( peak between 4-5 wks);
– Fetal period= teratogen can’t affect growth and maturation of organs; affects
mainly growth retardation
1. Interplay of Environment and genetics
– Cyclopramine ( from roots of California lily)  craniofacial anomalies in
lambs (affect hedgehog pathway),
– Valproic acid  disrupts highly conserved Homeobox proteins (patterning of
limbs, vertebrae, craniofacial structures)  valproic acid embryopathy
– Vitamin “A”  All – trans retinoic acid  essential for normal growth and
development of many organs ( eyes, genitourinary, CVS, diaphragm, lungs);
excess  retinoic acid embryopathy = CNS, CVS, Craniofacial and Cleft lip/
or palate): for cleft palate  deregulation of TGF – beta 3 gene


9

Rubin


Robbin’s


Table 10-3. National Prevalence Estimates for the Most Common Birth Defects in
Table 10-3. National Prevalence Estimates for the Most Common Birth Defects in
the United States, 1999-2001
the United States, 1999-2001
Birth Defect
CHROMOSOMAL DEFECTS

Estimated National Prevalence (per 10,000 live births)

Down syndrome (Trisomy 21)

12.8

Trisomy 13

1.3

Trisomy 18

2.3

OROFACIAL DEFECTS
Cleft palate

6.4

Cleft lip with and without cleft palate

10.5

CARDIOVASCULAR DEFECTS
Atrioventricular septal defect (endocardial cushion defect)

4.4

Transposition of great arteries

4.7

Tetrology of Fallot

3.9

CENTRAL NERVOUS SYSTEM DEFECTS
Spina bifida without anencephalus

3.7

Anencephalus

2.5

GASTROINTESTINAL DEFECTS
Rectal and large intestinal atresia/stenosis

4.8

Esophageal atresia/tracheoesophageal fistula

2.4

MUSCULOSKELETAL DEFECTS
Gastroschisis

3.7

Diaphragmatic hernia

2.9

Omphalocele

2.1

10.1 congenital anomalies; pediatric pathology

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10.1 congenital anomalies; pediatric pathology

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