11.1 Congenital disorders and birth defects

Congenital disorders and birth defects are developmental abnormalities that occur before birth. These conditions can result from genetic factors, environmental influences, or a combination of both, impacting the structure or function of various organ systems.

Understanding the causes and mechanisms of these disorders is crucial for improving prenatal diagnosis and developing potential interventions. This knowledge helps healthcare providers offer better genetic counseling, guide pregnancy management, and plan appropriate postnatal care for affected individuals.

Causes of Congenital Disorders

Genetic Factors

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• Single-gene mutations alter protein structure or function disrupting critical developmental pathways
• Chromosomal abnormalities lead to gene dosage imbalances affecting multiple developmental processes
  • Deletions or duplications of chromosomal segments
  • Aneuploidy (trisomies or monosomies)
• Complex inheritance patterns involve multiple genes interacting to produce developmental anomalies
• Advanced parental age increases risk of chromosomal abnormalities and certain genetic disorders
  • Maternal age particularly impacts risk of Down syndrome

Environmental Influences

• Maternal exposure to teratogens during critical periods of fetal development causes developmental abnormalities
  • Medications (thalidomide, isotretinoin)
  • Alcohol consumption leads to fetal alcohol spectrum disorders
  • Tobacco use increases risk of low birth weight and preterm birth
  • Infectious agents (rubella virus, Zika virus)
• Nutritional factors impact fetal development
  • Folic acid deficiency increases risk of neural tube defects (spina bifida)
  • Iodine deficiency leads to cretinism
  • Excessive vitamin A intake causes craniofacial abnormalities
• Maternal health conditions affect fetal development when not properly managed
  • Uncontrolled diabetes increases risk of cardiovascular and neural tube defects
  • Untreated phenylketonuria leads to intellectual disabilities in offspring

Gene-Environment Interactions

• Genetic susceptibility combined with environmental factors leads to manifestation of some congenital disorders
• Multifactorial inheritance involves both genetic predisposition and environmental triggers
  • Cleft lip and palate influenced by genetic factors and maternal smoking
  • Neural tube defects result from genetic susceptibility and folate deficiency
• Epigenetic modifications altered by genetic or environmental factors lead to abnormal gene expression during development
  • DNA methylation patterns affected by maternal diet and stress
  • Histone modifications influenced by environmental toxins

Classifying Congenital Disorders

Structural Birth Defects

• Physical abnormalities in organ systems or body parts visible at birth or detectable through imaging
• Cleft lip and palate results from incomplete fusion of facial structures
• Congenital heart defects involve structural abnormalities of the heart and major blood vessels
  • Ventricular septal defect
  • Tetralogy of Fallot
• Neural tube defects arise from incomplete closure of the embryonic neural tube
  • Spina bifida
  • Anencephaly

Functional Birth Defects

• Physiological process abnormalities without visible structural changes
• Metabolic disorders disrupt normal biochemical processes
  • Phenylketonuria impairs phenylalanine metabolism
  • Galactosemia affects galactose breakdown
• Sensory impairments affect vision, hearing, or other sensory functions
  • Congenital deafness
  • Retinitis pigmentosa
• Intellectual disabilities impact cognitive function and adaptive behavior
  • Fragile X syndrome
  • Prader-Willi syndrome

Chromosomal Disorders

• Abnormalities in chromosome number or structure lead to complex syndromes
• Numerical abnormalities involve extra or missing chromosomes
  • Down syndrome (trisomy 21) results from an extra copy of chromosome 21
  • Turner syndrome (monosomy X) occurs when one X chromosome missing in females
• Structural abnormalities involve changes in chromosome arrangement
  • Cri-du-chat syndrome caused by deletion on chromosome 5
  • Williams syndrome results from deletion on chromosome 7

Genetic Mechanisms of Developmental Anomalies

Gene Mutations and Protein Dysfunction

• Point mutations in developmental genes alter protein structure or function
  • Missense mutations change single amino acids affecting protein folding or activity
  • Nonsense mutations create premature stop codons leading to truncated proteins
• Disruption of critical signaling pathways essential for normal embryonic development
  • Sonic hedgehog pathway mutations cause holoprosencephaly
  • Fibroblast growth factor receptor mutations lead to craniosynostosis syndromes
• Alterations in genes controlling cell cycle, apoptosis, or differentiation disrupt tissue and organ formation
  • TP53 mutations increase risk of developmental defects and cancer predisposition

Chromosomal Aberrations and Gene Dosage

• Deletions or duplications result in gene dosage imbalances
  • 22q11.2 deletion syndrome leads to DiGeorge syndrome affecting multiple organ systems
  • Charcot-Marie-Tooth disease type 1A caused by duplication of PMP22 gene
• Translocations and inversions disrupt gene regulatory regions or create fusion genes
  • Philadelphia chromosome in leukemia results from translocation between chromosomes 9 and 22
• Aneuploidy causes widespread gene expression imbalances affecting multiple developmental processes
  • Trisomy 18 (Edwards syndrome) results in severe developmental abnormalities
  • Klinefelter syndrome (XXY) affects male sexual development and fertility

Epigenetic Modifications

• DNA methylation patterns influence gene expression during development
  • Abnormal methylation of imprinted genes leads to Prader-Willi and Angelman syndromes
• Histone modifications affect chromatin structure and gene accessibility
  • Mutations in histone-modifying enzymes cause Kabuki syndrome and Rubinstein-Taybi syndrome
• Environmental factors can alter epigenetic marks leading to developmental abnormalities
  • Maternal diet affects DNA methylation patterns in offspring
  • Exposure to endocrine disruptors alters histone modifications in developing germ cells

Importance of Prenatal Diagnosis

Screening and Detection Methods

• Non-invasive prenatal testing (NIPT) uses cell-free fetal DNA in maternal blood
  • Screens for common chromosomal abnormalities (trisomies 21, 18, and 13)
  • High sensitivity and specificity with low false-positive rates
• Invasive diagnostic procedures provide definitive genetic information
  • Amniocentesis samples amniotic fluid for fetal cell analysis
  • Chorionic villus sampling obtains placental tissue for genetic testing
  • Both carry small risk of pregnancy loss (0.1-0.5%)
• Advanced techniques expand range of detectable disorders
  • Whole-genome sequencing identifies rare genetic variants
  • Microarray analysis detects submicroscopic chromosomal abnormalities

Clinical Implications and Management

• Early detection guides pregnancy management and postnatal care planning
  • Fetal interventions for certain conditions (twin-to-twin transfusion syndrome)
  • Delivery planning for complex congenital anomalies
• Genetic counseling helps families understand implications of genetic disorders
  • Provides information on inheritance patterns and recurrence risks
  • Assists in making informed reproductive choices
• Identification of high-risk pregnancies enables targeted interventions
  • Increased monitoring for pregnancies with identified genetic abnormalities
  • Early initiation of therapies for manageable conditions (congenital adrenal hyperplasia)

Ethical Considerations and Future Directions

• Prenatal diagnosis raises ethical questions regarding selective termination
  • Balancing reproductive autonomy with societal perceptions of disability
• Advances in gene editing technologies (CRISPR-Cas9) open possibilities for in utero treatment
  • Potential for correcting genetic defects before birth
  • Ethical concerns regarding germline modifications
• Improving accessibility and equity in prenatal screening programs
  • Addressing disparities in access to advanced diagnostic technologies
  • Ensuring culturally sensitive genetic counseling and support services