CHROMOSOMAL ABNORMALITIES

MODERATOR INFORMATION

  • Moderator: Dr. Naveen Kumar

GROUP PARTICIPANTS

  • Group 6 Members:

    • Almas Natha (Tzm/15897)

    • Nuruddeen Ally (Tzm/15874)

    • Bokang Bamokwena Keetshabe (Tzm/15876)

    • Lontia Chashi (Tzm/15881)

    • Kristina Mwanda (Tzm/15877)

    • Dawn Makwana (Tzm/15983)

    • Joyce Khuziwe Katongo (Tzm/15906)

OBJECTIVES

  • To understand different types of chromosomal abnormalities.

  • To understand the clinical presentation and significance of chromosomal abnormalities.

WHAT ARE CHROMOSOMAL ABNORMALITIES?

  • Definition: Chromosomal abnormalities are genetic disorders caused by changes in chromosome number or structure, leading to abnormal gene dosage and altered development.

Major Types of Chromosomal Abnormalities

  • Numerical Abnormalities:

    • Aneuploidy

    • Polyploidy

  • Structural Abnormalities:

    • Deletions

    • Duplications

    • Inversions

    • Translocations

ANEUPLOIDY

  • Definition: Aneuploidy is a numerical chromosomal abnormality in which the chromosome number deviates from the normal diploid number (2n2n) due to gain or loss of one or a few chromosomes.

Causes of Aneuploidy

  • Nondisjunction during:

    • Meiosis I

    • Meiosis II

    • Mitosis

  • Mechanism: Failure of homologous chromosomes or sister chromatids to separate, resulting in unequal distribution to daughter cells which often leads to miscarriages or congenital disorders.

CLASSIFICATION OF ANEUPLOIDY

Types of Aneuploidy

  1. Hypoploidy: Cells have fewer than the normal number of chromosomes.

    • Subtypes:

    1. Monosomy (2n − 1):

      • Loss of one chromosome from a homologous pair

      • Usually lethal in autosomes

      • Example: Turner syndrome (45,X)

    2. Nullisomy (2n − 2):

      • Loss of an entire homologous chromosome pair

      • Typically lethal in diploid organisms, mainly observed in plants (e.g., wheat)

  2. Hyperploidy: Cells have more than the normal number of chromosomes.

    • Subtypes:

    1. Trisomy (2n + 1):

      • Presence of three copies of one chromosome

      • Types:

        • Full (primary) trisomy: extra complete chromosome

        • Partial trisomy: extra part of a chromosome

        • Secondary trisomy: extra iso-chromosome

        • Tertiary trisomy: arms from two different chromosomes

    2. Tetrasomy (2n + 2): Four copies of a specific chromosome; rare and often associated with severe developmental defects.

MECHANISM OF ANEUPLOIDY FORMATION

  • Aneuploidy primarily results from nondisjunction, the failure of chromosomes to separate properly during cell division.

  • Types of Nondisjunction:

    • Meiosis I Nondisjunction: Homologous chromosomes fail to separate.

    • Meiosis II Nondisjunction: Sister chromatids fail to separate.

    • Mitotic Nondisjunction: Occurs after fertilization and leads to mosaicism.

BENEFITS OF ANEUPLOIDY

  1. Genetic diversity & evolution:

    • Aneuploidy introduces new gene dosage patterns, increasing variation, which is the raw material for evolution and adaptation.

    • Some aneuploid states can persist in populations if they confer survival or reproductive advantages.

    • Important in plants, fungi, and microorganisms.

DRAWBACKS OF ANEUPLOIDY

  • Consequences:

    • Gene dosage imbalance

    • Developmental delay

    • Intellectual disability

    • Congenital anomalies

    • High rate of embryonic lethality

    • Reduced fertility

  • Cancer Cell Survival:

    • Many cancer cells are aneuploid, providing advantages such as:

    • Faster growth

    • Resistance to chemotherapy

    • Ability to invade tissues

    • Survival in low-oxygen or low-nutrient conditions

    • These traits benefit tumors but are harmful to patients.

DOWN SYNDROME

  • Definition: Down syndrome is a genetic condition caused when an unusual cell division results in an extra full or partial copy of chromosome 21. This extra genetic material causes developmental changes and physical features characteristic of Down syndrome.

Historical Context

  • Named after English physician John Langdon Down who first described the condition.

  • Most common cause of intellectual disabilities in children, commonly associated with congenital heart and digestive system problems.

IDENTIFYING DOWN SYNDROME IN INFANTS

Common Physical Traits:

  • Flat nasal bridge

  • Macroglossia and protruding tongue

  • Irregularly shaped mouth

  • Almond-shaped eyes due to an epicanthic fold of the eyelid

  • Microgenia

  • Single palmar crease

  • Curved short fifth finger

  • Upslanting palpebral fissures

  • Widely separated first and second toes

  • Increased skin creases

TYPES OF DOWN SYNDROME

Based on Chromosomal Patterns

  1. Trisomy 21:

    • Most common type where a person has three copies of chromosome 21.

    • Normal chromosome count is 46, so those with Down syndrome have 47 chromosomes.

  2. Translocation Down Syndrome:

    • Extra chromosome 21 material is attached to another chromosome.

    • Affected individuals may have 46 chromosomes.

    • About 3% of Down syndrome cases.

  3. Mosaic Down Syndrome:

    • Characterized by a mixture of cells with trisomy 21 and cells without the extra chromosome.

    • Symptoms may be milder; seen in about 2% of Down syndrome cases.

SYMPTOMS OF DOWN SYNDROME

  • Short stature

  • Skeletal differences

  • Heart malformations

  • Abnormal lung development

  • Intestinal malformations

  • Learning difficulties

  • Weak immune system

  • Hypothyroidism (low thyroid function)

CAUSES AND RISK FACTORS

  • The extra genetic material from the third copy of chromosome 21 causes physical developmental differences due to alterations in fetal development.

Risk Factors for Down Syndrome

  • Advanced Maternal Age: Especially significant for females aged 35 and older at the time of conception. Surrogate mothers below risk age do not reduce risk.

  • Family History: A history of Down syndrome or other chromosomal disorders in parents or siblings may increase risk.

COMPLICATIONS ASSOCIATED WITH DOWN SYNDROME

  • Scoliosis: Curvature of the spine due to physical differences.

  • Heart Failure: Insufficient blood pump due to heart defects, excessive weight, or low activity.

  • Bowel Obstruction: Can occur due to intestinal malformation.

  • Lung Aspiration: Possibility of drawing in foreign substances due to various contributing health issues.

  • Depression: Emotional challenges due to coping with limitations.

  • Increased Infection Risk: Medical complications such as severe effects from COVID-19 are common.

TYPICAL PHYSICAL FEATURES RELATED TO DOWN SYNDROME

  • Epicanthal folds and slanted palpebral fissures

  • Small, hypoplastic ears

  • Brushfield spots on iris

  • Short, broad hands, with a simian crease and clinodactyly of the fifth digit

  • Wide gap between first and second toes

KLINEFELTER SYNDROME

Overview

  • Definition: Klinefelter syndrome is a sex chromosome aneuploidy affecting males, defined by having one or more extra X chromosomes.

  • Most common karyotype: 47,XXY.

Genetic Basis

  • Caused by nondisjunction during meiosis in either maternal or paternal meiosis.

  • Leads to an abnormal number of sex chromosomes (aneuploidy).

  • Variants of Klinefelter syndrome include:

    • Mosaic form: 46,XY / 47,XXY

    • Severe forms: 48,XXXY, 49,XXXXY

  • Extra X chromosome leads to testicular dysgenesis, which results in:

    • Reduced testosterone production

    • Impaired spermatogenesis

    • Hypergonadotropic hypogonadism.

DIAGNOSIS

  • Often undiagnosed until puberty or adulthood.

MOSAIC KLINEFELTER SYNDROME

  • Two cell lines present: some are normal male (46,XY) while others show the Klinefelter pattern (47,XXY).

  • Symptoms tend to be milder due to relatively better testosterone levels and less severe infertility.

KLINEFELTER VARIANTS

  1. 48,XXXY:

    • Male with three X chromosomes and one Y.

    • Symptoms include: greater intellectual disability, more physical abnormalities, and severe hypogonadism.

  2. 49,XXXXY:

    • Male with four X chromosomes and one Y chromosome.

    • Rare and most severe form with significant developmental delay, skeletal abnormalities, and severe genital underdevelopment.

CLINICAL FEATURES OF KLINEFELTER SYNDROME

  • Physical Features:

    • Tall stature with long limbs (eunuchoid body habitus)

    • Small testes (testicular atrophy)

    • Sparse facial, axillary, and pubic hair

    • Gynecomastia (development of breasts)

    • Decreased muscle mass

  • Reproductive Features:

    • Delayed or incomplete puberty

    • Infertility due to azoospermia

  • Neurodevelopmental Features:

    • Intelligence often normal

    • Mild learning difficulties, especially in language and reading

    • Behavioral or social difficulties may occasionally occur.

DIAGNOSIS OF KLINEFELTER SYNDROME

  • Karyotyping: Confirms the presence of extra X chromosome.

  • Hormonal Assays: Show low testosterone and high LH and FSH levels, indicating the pituitary gland's attempt to stimulate the testes.

  • Semen Analysis: Typically shows no sperm contributing to infertility.

COMPLICATIONS AND MANAGEMENT OF KLINEFELTER SYNDROME

Complications:

  • Infertility

  • Osteoporosis

  • Metabolic syndrome and diabetes

  • Increased risk of breast cancer and autoimmune diseases (e.g., systemic lupus erythematosus).

Management:

  • Testosterone Replacement Therapy:

    • Promotes secondary sexual characteristics and improves muscle mass, libido, and bone density.

EDWARD’S SYNDROME

Definition

  • Also known as trisomy 18, Edward’s syndrome is a severe genetic condition affecting body development and growth, characterized by low birth weight, multiple birth defects, and distinctive physical features.

Types of Edward’s Syndrome:

  1. Complete Trisomy 18:

    • Most common form (~94%).

    • All cells have three full copies of chromosome 18 due to nondisjunction, typically maternal, with increasing risk correlated to maternal age.

    • Causes severe congenital abnormalities; usually results in early death.

  2. Mosaic Trisomy 18:

    • Less common (<5%), features a mixture of normal and trisomy 18 cells.

    • Severity varies based on the number of affected cells.

  3. Partial Trisomy 18:

    • Rare (~2%), involves duplication of part of chromosome 18q, often linked to parental balanced translocation.

    • Clinical features are dependent on the size/location of the duplicated segment.

CAUSES

  • Primary Cause: Nondisjunction leading to an extra chromosome 18, resulting in sperm or egg cells with an extra chromosome.

SYMPTOMS OF EDWARD’S SYNDROME

  • At Birth:

    • Low birth weight

    • Ears positioned lower on the head

    • Cleft lip/palate

    • Club foot

    • Heart, kidney, or spine issues

    • Breathing or digestion problems

DURING PREGNANCY:

  • Indicators:

    • Low fetal movement

    • Small placenta

    • Single umbilical artery

    • Polyhydramnios

    • Birth defects seen on ultrasound.

DIAGNOSIS

  • Prenatal Screening Tests: Maternal blood tests.

  • Invasive Procedures:

    • Chorionic villus sampling (CVS): 10–13 weeks

    • Amniocentesis: 15–20 weeks

  • Postnatal Chromosome Analysis: Confirms diagnosis.

TREATMENT OPTIONS

  • Cardiac Treatments: Most infants with Edward’s syndrome have heart problems; only a few qualify for surgical intervention.

  • Assisted Feeding: Infants may require feeding tubes for proper nutrition.

  • Orthopedic Treatment: Involves surgery/bracing for scoliosis and joint issues.

  • Psychosocial Support: Vital for coping with the emotional aspects of the diagnosis; support in navigating loss or complexity.

  • Individualized Approach: Treatment plans are tailored based on severity.

PATAU SYNDROME

Definition

  • Autosomal Aneuploidy: Resulting from an extra chromosome 13.

  • Karyotype: 47,XX/XY,+13.

Key Features

  • Common Features:

    • Cleft lip and palate

    • Microphthalmia (abnormal eye size)

    • Polydactyly (extra fingers/toes)

    • Severe intellectual disability

    • Congenital heart defects.

  • Prognosis: Generally poor; most infants do not survive past the first year of life.

REFERENCES

  • Ross, J.L., Roeltgen, D.P., Kushner, H. et al. (2012). Cognitive and motor development during childhood in boys with Klinefelter syndrome. American Journal of Medical Genetics Part A, 158A(11), pp. 2720–2729.

  • Leggett, V., Jacobs, P., Nation, K., Scerif, G., and Bishop, D.V.M. (2010). Neurocognitive outcomes of individuals with sex chromosome trisomies: XXX, XYY, and XXY. Developmental Medicine & Child Neurology, 52(2), pp. 119–129.

CLOSING

  • Thank You!