Embryology

Overview of Dysmorphology

  • Topic: Study of congenital anomalies
  • Presenter: Awolola A M
  • Institution: Anatomy Programme of Bowen University, Iwo
  • Date: 27th May, 2024

Outline

  • Registers
  • Introduction
  • Historic timeline
  • Epidemiology
  • Types
  • Aetiology
  • Pathophysiology
  • Prevention and intervention
  • Fetal therapy
  • References

Registers

  • Birth defects: Also known as congenital malformations or congenital anomalies. These encompass:
    • Structural disorders
    • Behavioral disorders
    • Functional disorders
    • Metabolic disorders
    • Present at birth
  • Teratology: Derived from the Greek word "teratos" meaning monster. It describes the study of these congenital disorders.
    • Definition from Merriam-Webster.com Medical Dictionary.

Introduction

  • Teratology: It refers to the study of congenital disorders impacting functionality, structure, behavior, and metabolism at birth.
  • Epidemiology: This field highlights that congenital disorders have a global incidence and remain a leading cause of infant mortality.
    • Understanding teratology is crucial for prevention, diagnosis, and treatment of these disorders.
  • Aetiology: Factors contributing to congenital anomalies can be genetic, environmental, or multifactorial, requiring more invasive procedures for definitive diagnosis.
    • Noninvasive prenatal screenings are available prior to definitive diagnosis (Sadler, Thomas W., Langman, Jan. 2010).

Medical Advances Overview

  • Modern advancements allow for fetal management like treatments for conditions through:
    • Fetal transfusions
    • Administration of medications
    • Gene therapy
    • Surgical interventions
  • Types of surgical procedures:
    • Open fetal surgery: Involves incising the uterus for defect repair (e.g., VACTERL defects)
    • Fetoscopy: A less invasive approach using endoscopy to place shunts or repair issues like amniotic bands or less severe diaphragmatic hernias (Sadler, Thomas W., Langman, Jan. 2010).

Congenital Anomalies: Cranial & Spinal Birth Defects

  • Examples of Neural Tube Defects (NTDs):
    • Spina bifida
    • Anencephaly
    • Encephalocele

Spinal Birth Defects

  • Spina Bifida: Occurs mainly due to a deficiency in folic acid; linked to incomplete neural tube fusion at the caudal end on the 28th day of intrauterine life (IUL).
    • Types of Spina Bifida:
    • Spina Bifida Occulta
    • Meningocele
    • Myelomeningocele

Other Congenital Defects

  • Bladder exstrophy
  • Horseshoe Kidney
  • Polycystic Kidney

Specific Teratogenic Agents

Thalidomide

  • Introduced in the 1950s and 1960s as a sedative and for cough suppression during pregnancy.
  • Discovered to cross the placenta resulting in serious congenital defects.
  • Increased incidence of amelia (absence of limbs) and meromelia (partial absence of limbs), affecting 5000-7000 neonates (Kim and Scialli, 2012).

Fetal Alcohol Syndrome (FAS)

  • Most common preventable cause of adverse CNS development.
  • Incidence: 4000–12000 neonates per year in the US.
  • Characterized by:
    • Mental retardation
    • Significant structural and functional neurological impairments
    • Distinct facial malformations:
    • Short palpebral fissures
    • Smooth philtrum
    • Thinner upper lip
    • Growth deficiencies including low birth weight, microcephaly (Dejong et al., 2019).

Epidemiology of Congenital Anomalies

  • Approximately 3% of live births experience congenital anomalies.
  • Congenital disorders contribute to about 25% of infant mortality, making them a significant public health concern.
  • Congenital anomalies are a major contributor to disabilities.

Types of Congenital Anomalies

  • Structural Anomalies:

    • Example conditions:
    • V: Spina bifida
    • A: Imperforate anus, anorectal fistula
    • C: Tetralogy of Fallot
    • T: Tracheoesophageal fistula
    • E: Agenesis or ectopic conditions
    • L: Club foot

  • Functional Defects:

    • Examples:
    • Metabolic disorders like alkaptonuria, phenylketonuria
    • Neurological conditions such as spina bifida

  • Genetic Anomalies:

    • Examples include Down syndrome and sickle cell anemia.

Aetiology of Congenital Anomalies

  • Breakdown of contributing factors:
    • Genetic: 30%
    • Environmental: 15%
    • Multifactorial: 55%

Genetic Factors

  • Key components include:
    • Mutations
    • Inherited conditions

Environmental Factors

  • Exposure to potential teratogens, including:
    • Toxins
    • Ionizing radiation
    • Maternal infections (e.g., viruses such as rubella, cytomegalovirus (CMV), herpes simplex virus (HSV), Zika, and varicella; protozoa like Toxoplasma gondii)
    • Maternal health issues such as diabetes, hypertension, and malnutrition
    • Chemical agents (industrial and agricultural chemicals)
    • Pharmaceutical drugs

Chemical Agents

  • Industrial chemicals: Lead
  • Agricultural chemicals: Mercury and pesticide residues (herbicides, insecticides like organochlorates, organophosphates)
  • Food additives: Methyl mercury
  • Recreational drugs: Alcohol, tobacco, cocaine, solvents

Pharmaceutical Drugs

  • Key examples include:
    • Anticonvulsants (phenytoin, valproic acid, trimethadione)
    • Note: Trimethadione and fetal hydantoin syndrome related to distinct dysmorphogenesis and facial clefts.
    • Newer agents like Topiramate are also implicated.
    • Antipsychotics and anxiolytics
    • Antidepressants (SSRIs such as fluoxetine, citalopram)
    • Antitussives such as ondansetron
    • Opioids like hydrocodone
    • Anticoagulants (heparin)
    • Antihypertensives (ACE inhibitors)
    • Hormones (e.g., DES)

Nutritional Factors

  • Nutritional deficiencies:
    • Endemic cretinism associated with iodine deficiency

Risk of Birth Defect Induction

  • Stages of gestation affecting risk:
    • Before the 3rd week (embryonic disc)
    • 3rd to 8th week (embryonic period)
    • 9th week to term (fetal period)
  • Embryonic disc: Insults during this stage lead to a binary outcome of either spontaneous abortion or embryonic death.
  • Embryonic period: Insults in this window lead to anomalies as this period coincides with organogenesis (formation of organs).
    • Critical axis formation begins late in the first week at the blastocyst stage, which can lead to disruptions in cellular signaling.

Specific Conditions Related to Risk

  • Situs Solitus: Normal axial alignment.
  • Situs Inversus: Mirror image of normal arrangement, with increased risk of cardiac defects but not other anomalies.
  • Situs Ambiguity (heterotaxy): More serious risk for defects, including midline malformations (Sadler, T. W., 2010).

Pathophysiology of Teratogenesis

  • Key mechanisms identified include:
    • Disruptions
    • Altered gene expression
    • Mutations and epigenetic modifications

Prevention and Intervention

  • Prenatal Counseling: Essential in managing congenital anomalies.
  • Prenatal Screening: Helps identify conditions early.
  • Prenatal Diagnosis: Includes a range of testing options:
    • Invasive procedures such as:
    • Amniocentesis
    • Chorionic villus sampling
    • Cordocentesis or percutaneous umbilical blood sampling (PUBS)
    • These procedures isolate cell-free fetal DNA (cfDNA) for sequencing to detect genetic abnormalities (Sadler, T. W., 2010).

Fetal Therapy Options

  • Fetal Transfusion: For treating anemia or other blood-related issues.
  • Fetal Medical Treatments: Addressing various congenital conditions.
  • Fetal Surgery:
    • Fetoscopy: Minimally invasive technique for conditions like placing shunts, severing amniotic bands, or repairing small diaphragmatic hernias.
    • Open Surgery: More invasive but necessary for some defects.
    • Stem Cell Transplantation and Gene Therapy: Potential for changing the prognosis of certain congenital conditions (Sadler, T. W., 2010).

Future Directions in Prevention

  • Focus on enhancing prenatal counseling, screening, diagnosis, and interventions to improve outcomes for affected neonates.

References

  • Dejong K, Olyaei A, Lo JO (2019). "Alcohol Use in Pregnancy" Clinical Obstetrics and Gynaecology. 62(1): 142-155.
    DOI: 10.1097/GFR.000000000000414
    PMC 7061927.
  • Kim JH, Scialli AR. Thalidomide: the tragedy of birth defects and effective treatment of diseases. Toxicol Sci. 2022 Jul;122(1): 1-6.
    DOI: 10.1093/toxsci/kfr088.
  • Merriam-Webster.com Medical Dictionary. "Dysmorphology" https://www.Merriam-Webster.com/medical/dysmorphology. Accessed 12 July, 2024.
  • Sadler, Thomas W., Langman, Jan. (2010). Langman’s Medical Embryology / T.W. Sadler; original illustrations by Jill Leland.