Chromosomal Abnormalities: Down Syndrome, Patau, Edward, Turner & Klinefelter Syndromes

Posted on Apr 28, 2024 in Biology

Chromosomal Abnormalities

Down Syndrome

Clinical Features:

  • Hypotonia (low muscle tone)
  • Dysmorphic facial features:
    • Flat nasal bridge
    • Low-set ears with a characteristic folded appearance
    • Brushfield spots around the margin of the iris
    • Open mouth, often showing a furrowed, protruding tongue
    • Epicanthal folds and upslanting palpebral fissures
  • Short stature
  • Brachycephaly (short, broad head) with a flat occiput
  • Short neck with loose skin on the nape
  • Short, broad hands with incurved fifth digits (clinodactyly)
  • Wide gap between the first and second toes
  • Mental retardation
  • Congenital heart disease

Chromosomal Basis:

  1. Trisomy 21: Most common form (about 95% of cases), involving an extra copy of chromosome 21. Maternal age over 30 is a risk factor.
  2. Partial Trisomy 21: Rare form where only a part of chromosome 21 is present in triplicate.
  3. Robertsonian Translocation: About 4% of cases, involving a translocation between chromosome 21 and another chromosome.
  4. 21q21q Translocation: Rare form involving a translocation between two copies of chromosome 21.
  5. Mosaic Down Syndrome: Rare form with a mixture of cells with and without trisomy 21.

Recurrence Risk:

  • After one child with Down syndrome, the risk is about 1% and increases with maternal age.

Patau Syndrome (Trisomy 13)

Clinical Features:

  • Growth retardation and severe mental retardation
  • Holoprosencephaly (failure of the forebrain to divide properly)
  • Microcephaly (small head) with a sloping forehead
  • Wide open sutures (soft spots) in the skull
  • Malformations of the ears
  • Cleft lip and/or cleft palate
  • Postaxial polydactyly (extra fingers or toes)
  • Rocker-bottom feet
  • Congenital heart defects
  • Urogenital defects
  • Polycystic kidneys

Cause:

  • Nondisjunction in maternal meiosis

Recurrence Risk:

  • Low, less than 2%

Edward Syndrome (Trisomy 18)

Clinical Features:

  • Mental retardation and failure to thrive
  • Severe malformations of the heart
  • Hypertonia (increased muscle tone)
  • Prominent occiput (back of the head)
  • Receding jaw
  • Low-set, malformed ears
  • Short sternum (breastbone)
  • Clenched fists
  • Rocker-bottom feet
  • Distinctive dermal patterns with single palmar creases and arch patterns on most or all digits
  • Hypoplastic (underdeveloped) nails
  • Poor postnatal survival (few months)
  • More common in females than males

Risk Factors:

  • Maternal age over 35

Causes:

  1. Trisomy 18
  2. Translocation of chromosome 18

Turner Syndrome (45,X)

Cause:

  • Lack of one X chromosome

Clinical Features:

Physical:
  • Short stature
  • Ovarian failure
  • Lack of pubic hair
  • Webbed neck
  • Cubitus valgus (increased carrying angle of the elbow)
  • Shield chest (widely spaced nipples)
  • Lymphedema (swelling) of the hands and feet
  • Ptosis (drooping eyelids)
  • High blood pressure (due to coarctation of the aorta)
  • Thyroid problems
Genetic:
  • Low risk of recurrence
  • Infertility
  • Can be diagnosed prenatally
  • Parents should be tested for Y chromosome material

Klinefelter Syndrome (47,XXY)

Cause:

  • Extra X chromosome
  • Nondisjunction in meiosis

Clinical Features:

  • Infertility and gynecomastia (breast enlargement)
  • Fatigue, weakness, osteoporosis, language difficulties
  • Increased height
  • Normal head size and weight
  • Normal intelligence, but some learning disabilities
  • Behavioral problems, anxiety, depression, neurosis, psychosis
  • Lack of secondary sexual characteristics due to androgen deficiency
  • Lack of facial hair
  • High-pitched voice
  • Testicular dysgenesis (infertility)
  • Atrophy of seminiferous tubules
  • Mitral valve prolapse (55%)
  • Varicose veins

Genetic Counseling:

  • To avoid recurrence
  • Follow-up on the child

Genetic Counseling

Indications for Genetic Counseling:

  • Previous child with multiple congenital anomalies
  • Family history of a hereditary condition
  • Prenatal diagnosis for advanced maternal age or other indications
  • Consanguinity
  • Teratogen exposure
  • Repeated pregnancy loss or infertility
  • Before and after genetic testing
  • Follow-up for a positive newborn screening test

Principles of Genetic Counseling:

  1. Information gathering: Family history, medical history, tests, and assessments
  2. Counseling: Discussing options, risks, and benefits
  3. Assessment: Physical examination, laboratory tests, and imaging studies
  4. Diagnosis: Establishing a diagnosis if possible
  5. Decision-making: Discussing options and making informed choices
  6. Referral: To other specialists, health agencies, and support groups
  7. Continuing assessment and psychosocial support

Genetic Screening Programs

Requirements for a Population Screening Program:

  1. Positive result must lead to some useful action (e.g., treatment, reproductive options)
  2. Socially and ethically acceptable with informed consent and counseling
  3. High sensitivity and specificity of the test
  4. Benefits outweigh costs

Types of Genetic Screening:

  • Neonatal screening: Screening newborns for certain genetic disorders (e.g., phenylketonuria)
  • Prenatal screening: Screening during pregnancy for certain genetic disorders (e.g., Down syndrome)
  • Carrier screening: Screening individuals for carrier status of certain genetic disorders (e.g., cystic fibrosis)

Invasive Prenatal Diagnostics

Chorionic Villus Sampling (CVS):

  • Performed at 10-12 weeks of pregnancy
  • Biopsy of the placenta
  • Results take about 2 weeks
  • Complications: bleeding, miscarriage, maternal contamination, confined placental mosaicism

Amniocentesis:

  • Aspiration of amniotic fluid for analysis
  • Performed at 15-17 weeks of gestation
  • Results take 2-4 weeks
  • Complications: failure to aspirate fluid, amniotic fluid leakage, miscarriage, fetal injury

Fetal Blood Sampling:

  • Percutaneous puncturing of the umbilical cord
  • Performed from 17 weeks of gestation to near term
  • Results available in 48 hours
  • Used for urgent karyotyping, viral or bacterial cultures, and hematologic indices
  • Complications: fetal loss, fetal bleeding, fetal bradycardia

Noninvasive Prenatal Diagnostics

Methods:

  • Ultrasonography
  • Maternal serum alpha-fetoprotein
  • First- and second-trimester maternal serum screening
  • Isolation of fetal cells from maternal circulation

Ultrasonography:

  • Detects abnormal fluid accumulation in the fetal neck (nuchal translucency)
  • Increased nuchal translucency is associated with trisomies 21, 13, and 18, and 45,X

Biochemical Markers:

  • Maternal serum alpha-fetoprotein (MSAFP): Elevated levels may indicate neural tube defects or abdominal wall defects. Low levels may indicate Down syndrome.
  • First- and second-trimester maternal serum screening: Measures various biochemical markers in maternal blood to assess the risk of certain chromosomal abnormalities.

Dysmorphology

Definitions:

  1. Malformation: Morphological defect of an organ or part of an organ due to an abnormal developmental process.
  2. Disruption: Morphological defect resulting from the extrinsic breakdown of a normal developmental process.
  3. Deformation: Abnormality of form or position of a body part caused by mechanical forces.
  4. Dysplasia: Morphological defect caused by abnormal organization of cells into tissue.
  5. Sequence: Pattern of multiple anomalies derived from a single prior anomaly or mechanical factor.
  6. Syndrome: Pattern of multiple anomalies thought to be pathogenically related.
  7. Developmental field defect: Pattern of anomalies resulting from the disturbed development of a morphogenetic field.
  8. Association: Nonrandom grouping of congenital anomalies that occur together more frequently than expected by chance.

Single Gene Disorders

Autosomal Recessive Inheritance:

  • Condition is usually seen in a single generation.
  • Carriers are usually unaffected.
  • Recurrence risk for offspring of two carrier parents is 25%.
  • Consanguinity increases the risk.

Autosomal Dominant Inheritance:

  • Risk of transmission to each child is 50%.
  • Male-to-male transmission is possible.
  • Condition is often seen in multiple generations.
  • Reduced penetrance and variable expressivity are common.

Multifactorial Inheritance

Characteristics:

  • Familial but does not follow a monogenic pattern of inheritance.
  • May be more common in one sex.
  • Recurrence risk is the same for relatives who share the same proportion of genes.
  • Recurrence risk decreases as the relationship to an affected individual becomes more remote.
  • More common among children of consanguineous parents.
  • Concordance in monozygotic twins is less than 100%.

Factors Affecting Recurrence Risk:

  • Number of affected relatives
  • Severity of the condition in affected relatives

Diagnosis:

  • Diagnosis of exclusion

Genetic Disease Treatment Principles

Pre-Genetic Medicine Era:

  • Metabolic manipulation:
    • Diet modification
    • Stimulating expression of substitute proteins
    • Upregulating expression of mutant proteins
  • Protein augmentation therapy: Replacing missing proteins

Post-Genetic Medicine Era:

  • Somatic stem cell therapy:
    • Hematopoietic stem cell transplantation
    • Non-hematopoietic stem cell transplantation
  • Gene therapy:
    • Ex vivo gene therapy
    • In vivo gene therapy
    • Gene transfer vectors (viral and non-viral)
  • RNA modification therapy:
    • Antisense oligonucleotides
    • RNA interference (RNAi)
    • Trans-splicing
    • Ribozymes