10.1 congenital anomalies; pediatric pathology
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Transcript of 10.1 congenital anomalies; pediatric pathology
Pediatric PathologyTopics
Pediatric PathologyTopics
Dr. Krishna Tadepalli, MD, www.mletips.com
Table 10-1. Cause of Death Related with AgeCauses* Rate†
UNDER 1 YEAR 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
Accidents and adverse effects
Malignant neoplasms
Homicide and legal intervention
Congenital malformations, deformations, and chromosomal abnormalities
Suicide
Diseases of the heart
15-24 YEARS 80.1
Accidents and adverse effects
Homicide
Suicide
Malignant neoplasms
Diseases of the heart Dr. Krishna Tadepalli, MD, www.mletips.com
1. Congenital Anomalies1. Congenital Anomalies
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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)
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MalformationsMalformations
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Disruptions Disruptions
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Sequence Sequence
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Potter Sequence Potter Sequence
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Syndrome (what is it?)Syndrome (what is it?)
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Congenital Anomalies• Others6. Agenesis= Complete absence of the organ and its primordium7. Aplasia = also like agenesis (absence of the organ) but due to failure of primordial
development8. Atresia = absence of opening of hollow visceral organ (Trachea, Duodenum)9. Hypoplasia = Incomplete development or decrease in size of organ with decrease in
# of cells10. Dysplasia = abnormal or disorganization of cells
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Congenital Anomalies• 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)
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Table 10-2. Causes of Congenital Anomalies in HumansTable 10-2. Causes of Congenital Anomalies in HumansCause 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
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Drugs (Phacomelia= ? drug)Drugs (Phacomelia= ? drug)
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DilantinDilantin
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Spina bifida – neural tube defect ? drugSpina bifida – neural tube defect ? drug
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Congenital Anomalies• Pathogenesis of Anomalies1. 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
2. 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
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Rubin
9
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Robbin’s Dr. Krishna Tadepalli, MD, www.mletips.com
Table 10-3. National Prevalence Estimates for the Most Common Birth Defects in the United States, 1999-2001
Table 10-3. National Prevalence Estimates for the Most Common Birth Defects in the United States, 1999-2001
Birth Defect Estimated National Prevalence (per 10,000 live births)
CHROMOSOMAL DEFECTS
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
Dr. Krishna Tadepalli, MD, www.mletips.com