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10.1 congenital anomalies; pediatric pathology


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10.1 congenital anomalies; pediatric pathology

  1. 1. Pediatric Pathology Pediatric Pathology Topics Topics Dr. Krishna Tadepalli, MD,
  2. 2. 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 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,
  3. 3. 1. Congenital Anomalies 1. Congenital Anomalies Dr. Krishna Tadepalli, MD,
  4. 4. 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) Dr. Krishna Tadepalli, MD,
  5. 5. Malformations Malformations Dr. Krishna Tadepalli, MD,
  6. 6. Disruptions Disruptions Dr. Krishna Tadepalli, MD,
  7. 7. Sequence Sequence Dr. Krishna Tadepalli, MD,
  8. 8. Potter Sequence Potter Sequence Dr. Krishna Tadepalli, MD,
  9. 9. Syndrome (what is it?) Syndrome (what is it?) Dr. Krishna Tadepalli, MD,
  10. 10. Congenital Anomalies • 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 Dr. Krishna Tadepalli, MD,
  11. 11. 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) Dr. Krishna Tadepalli, MD,
  12. 12. 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 Dr. Krishna Tadepalli, MD,
  13. 13. Drugs (Phacomelia= ? drug) Drugs (Phacomelia= ? drug) Dr. Krishna Tadepalli, MD,
  14. 14. Dilantin Dilantin Dr. Krishna Tadepalli, MD,
  15. 15. Spina bifida – neural tube defect ? drug Spina bifida – neural tube defect ? drug Dr. Krishna Tadepalli, MD,
  16. 16. Congenital Anomalies • 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 Dr. Krishna Tadepalli, MD,
  17. 17. 9 Rubin Dr. Krishna Tadepalli, MD,
  18. 18. Robbin’s Dr. Krishna Tadepalli, MD,
  19. 19. 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 Dr. Krishna Tadepalli, MD,