Pathogenesis of congenital anomalies

1. Definition

Congenital anomalies are structural or functional defects present at birth (sometimes manifesting years later). They are a leading cause of infant mortality, illness, and disability. A major anomaly has cosmetic or functional significance.

2. Terminology

Term	Meaning
Malformation	Intrinsically abnormal developmental process (usually multifactorial)
Disruption	Secondary destruction of a previously normal organ (extrinsic)
Deformation	Extrinsic mechanical compression (e.g. uterine constraint)
Dysplasia	Abnormal cellular organization within a tissue
Sequence	Multiple anomalies from one localized aberration
Agenesis / Aplasia / Hypoplasia	Absent / incomplete / underdeveloped organ
Atresia	Absence of an opening (duct/hollow organ)

3. Etiology (3 categories)

• Genetic — chromosomal aberrations (mostly from gametogenesis, not familial) and Mendelian single-gene mutations (familial).
• Environmental:
  • TORCH infections (Toxoplasma, Other, Rubella, CMV, Herpes) — transplacental, transcervical, or via birth canal.
  • Maternal disease — diabetes (↑ fetal organ/body mass), PKU, endocrinopathies.
  • Drugs/teratogens — warfarin, thalidomide, folic-acid antagonists, 13-cis-retinoic acid.
  • Alcohol → fetal alcohol syndrome (pre-/postnatal growth retardation, facial anomalies, psychomotor disturbance).
  • Smoking → low birth weight, spontaneous abortion, placental abnormalities.
• Multifactorial — environment + multiple small-effect genes.

4. Pathogenesis — timing of insult

Period	Effect
First 3 weeks (pre-embryonic)	“All or none” — death/abortion, or full recovery
Weeks 3–9 (organogenesis)	Most susceptible to teratogenesis → major structural defects
Weeks 9–42 (fetal)	Lower susceptibility → growth retardation / injury to formed organs

Mechanisms include failure of neural tube closure, abnormal cell migration/differentiation, disordered apoptosis, and vascular disruptions.

💡 High-yield: Malformation (intrinsic) vs disruption (extrinsic destruction) vs deformation (mechanical) vs dysplasia (organization). Causes = genetic + environmental + multifactorial; TORCH, maternal diabetes, alcohol (FAS), retinoids. Weeks 3–9 (organogenesis) = peak teratogen sensitivity.