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


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

1. Congenital Anomalies1. 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)


MalformationsMalformations


Disruptions Disruptions


Sequence Sequence


Potter Sequence Potter Sequence


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


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


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)


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


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


DilantinDilantin


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


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


Rubin

9


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


10.1 congenital anomalies; pediatric pathology

Health & Medicine

Transcript of 10.1 congenital anomalies; pediatric pathology