Definitions

• teratology – “the study of monsters”, the science of congenital malformations
• Teratogenesis – 1) the path. Process resulting in a malformation 2) cell injury, mitotic arrest, or impeded gene-enzyme activation resulting in structural or functional malformation
• Congenital Malformation – a structural defect present at birth with or without a genetic defect
• Congenital anomaly – includes malformations but also abnormal behavior, function, and chemistry
• Malformation – a morphological defect of an organ or body region due to an intrinsically abnormal process
• Disruption – morphological defect due to extrinsic interference with normal developmet; implies a 2^o defect.
• Deformation – abnormal form, shape, or position due to mechanical interference with normal development
• Dysplasia – abnormal organization of cells into tissues; usually involves connective tissue and is widespread rather that confined to an organ

Incidence of Teratogenosis

• difficult to tell because of huge variety of ascertainment
• approx. 1-2% of all liveborn term infants have lethal or non-lethal congenital malformations
• Congenital malformations account for 30-40% of hospital admissions and about 20,000 deaths per year in the US.

Etiology of Congenital Malformations

• Teratogen – ~10%
• Hereditary, familial, or genetic – ~20%
• Chromosommal aberration – ~3-5%
• Unknown – ~65%

Teratogenic Agents

1)     Vitamin deficiencies: A, riboflavin, niacin, pantothenic acid, folic acid, etc)

2)     Antimetabolites

3)     Alkylating agents

4)     Antibiotics: Mitomycin, actinomycin, puromycin

5)     Salicylates, azo dyes, thalidomide

Susceptibility of the embryo to a teratogen

• early embryonic period (0-14 days) – relatively impervious
• during gastrulation and germ layer formation (2-8 weeks) – maximum susceptibility

Ø  gastrulation causes great structural instability

• Once organogenesis is complete the fetus responds to injury by growth retardation or inflammation

Environmental Teratogens

• Viruses

Ø  TORCH – especially Rubella

• X-Ray

Ø  poorly defined role

Ø  causes congenital malformations in 60% of patients: microcephaly, skull defects, spina bifida, blindness, cleft palate, micromelia, club foot

Drugs and Chemicals

Ø  Thalidomide

-        critical period – between day 37 and 50

-        causes: phocomelia, ear, gut, and heart abnormalities

Ø  Cancer Chemo

-        aminopterin, 6-MP, Busulfan, Nitrogen Mustard

Ø  Steroids

-        masculinization of the femal fetus

-        questionable increase in the incidence of cleft palate

Ø  Diethylstilbestrol

-        vaginal malformations in females

-        epididymal cysts in males

-        clear cell carcinoma of the vagina at adolescence

Mendelian Inheritance

• Autosomal Dominant: single malformation or syndromes

Ø  Marfan’s syndrome, neurofibromatosis

• Autosomal recessive: most often are enzyme defects, inborn errors of metabolism
• Sex linked – imperforate anus, congenital cataract

Multifactorial Inheritance

• genetics + environment

Cytogenic Abnormalities

• autosomal chromosomal abnormalities
• Sex chromosome abnormalities

REPRESENTATIVE CONGENITAL MALFORMATIONS

Tracheo-esophageal fistula

• hydramnios with esophageal atresia
• Most common form (90%) – esophageal atresia with tracheal fistula with the lower segment
• Usual site of fistula – 0.5 cm above carina
• 50% have associated malformations; CHD in 25%

Hypertrophic pyloric Stenosis

• usually appears clinically postnatally 2-3 weeks
• 10% have associated malformations
• MICRO:

Ø  hypertrophy of circular muscle with compression of mucosa and obliteration of lumen.

Ø  Mucosa may become edematous.

Intestinal Atresia

• Duodenal

1)     usually located at or distal to ampulla of Vater

2)     50% have associated malformations: high assoc with Down’s

3)     usually true “developmental defect”

• Jejunum and ileum

1)     approx 15% are multiple

2)     hydramnios is frequent

3)     may follow intrauterine volvulus, intussusception, meconium ileus, NEC

4)     ischemia is considered the basis; acquired defect

• Rare in colon, except after NEC

Meckel’s Diverticulum

• incidence of approx 1/50
• 50% are asymptomatic
• symptoms

1)     bleeding, intestinal obstruction

• Location: antimesenteric border of ileum, 20-35 cm proximal to ileocecal valve
• May retain attachment to omphalomesenteric duct and present at the umbilicus as a granuloma
• Gastric epithelium located in 50% of specimens

Hirschsprung Disease

• Incidence 1/5000 births
• 80% are amle
• Down syndrome in 2-3% of cases
• Symptoms

1)     failure to mass meconium

2)     chronic constipation

3)     abdominal distention

4)     vomiting and diarrhea

• Prognosis

1)     75-95% survival rate

2)     Agangliosis of entire colon – 75-85% MORTALITY

• MICRO

1)     absence of ganglion cells from submucosal (Meissner’s) and intermuscular (Auerbach’s) plexuses

2)     hypertrophy of muscularis mucosa

3)     constricted, distal segment is abnormal

4)     diagnosis by biopsy of distal segment

Diaphragmatic Herniaa

• most common on LEFT, posterolateral: foramen of Bachdalek
• non-operative mortality – close to 100%
• unilateral pulmonary hypoplasia
• Eventration

Tags: aminopterin, Antimetabolites, Autosomal, Congenital Malformation, Congenital Malformations, Cytogenic Abnormalities, Diaphragmatic Herniaa, Diethylstilbestrol, Dysplasia, Hirschsprung Disease, Hypertrophic pyloric Stenosis, Intestinal Atresia, Meckel's diverticulum, Mendelian Inheritance, Teratogenesis, teratology, thalidomide, Tracheo-esophageal fistula

This entry was posted on Thursday, July 2nd, 2009 at 5:00 am and is filed under Pathophysiology. You can follow any responses to this entry through the RSS 2.0 feed. Responses are currently closed, but you can trackback from your own site.