Chromosomal Disorders

Chromosomal Disorders - Blueprint Blips

• Alterations in chromosome number (numerical) or structure, leading to genetic syndromes.
• Numerical Abnormalities:
  • Aneuploidy: Abnormal chromosome number (e.g., trisomy, monosomy). Common mechanism: Nondisjunction (failure of chromosome/chromatid separation during meiosis/mitosis).
  • Polyploidy: Presence of >2 complete sets of chromosomes (e.g., triploidy 69,XXX).
• Structural Abnormalities: Deletions, duplications, translocations, inversions.
• Mosaicism: Two or more cell lines with different chromosomal constitutions in one individual.
• Nomenclature: e.g., $47,XX,+21$ (female with Trisomy 21).

⭐ Trisomy 21 (Down syndrome) is the most common autosomal aneuploidy compatible with postnatal survival, occurring in approximately 1 in 700 live births globally.

Chromosomal Disorders - Extra Chromosome Dramas

• Down Syndrome (Trisomy 21): Most common autosomal trisomy.

  • Clinical Features: Upslanting palpebral fissures, epicanthal folds, Brushfield spots (iris), flat nasal bridge, single transverse palmar crease (simian crease), hypotonia. Intellectual disability.
  • Cardiac: Atrioventricular septal defect (AVSD), VSD.
  • GI: Duodenal atresia, Hirschsprung disease.
  • Screening:
    • 1st Trimester: ↓PAPP-A, ↑free β-hCG, ↑nuchal translucency.
    • 2nd Trimester (Quad screen): ↓AFP, ↓estriol, ↑hCG, ↑inhibin A.
  • Associated: Hypothyroidism, ↑risk of ALL/AML, early-onset Alzheimer's.
  • 📌 Mnemonic (My Child Has Problems): Multiple anomalies, Cardiac defects, Hypotonic, Palmar crease.

• Edwards Syndrome (Trisomy 18):

  • Features: Micrognathia, low-set ears, prominent occiput, clenched hands (overlapping fingers), rocker-bottom feet, severe intellectual disability, congenital heart defects. Poor prognosis.

• Patau Syndrome (Trisomy 13):

  • Features: Midline defects (holoprosencephaly, cleft lip/palate), microphthalmia, polydactyly, scalp defects (cutis aplasia), congenital heart defects. Severe intellectual disability. Very poor prognosis.

⭐ Most common cardiac defect in Down Syndrome is Atrioventricular Septal Defect (AVSD), also known as endocardial cushion defect. However, VSD is also very common overall in these patients.

Chromosomal Disorders - X & Y Tales

• Turner Syndrome (45,XO):
  • Features: Short stature, webbed neck (pterygium colli), broad chest (shield chest), ovarian dysgenesis (streak gonads, infertility, amenorrhea), coarctation of aorta, cystic hygroma.
  • 📌 Mnemonic: CLOWNS (Cardiac, Lymphoedema, Ovaries, Webbed neck, Nipples wide, Short stature).
• Klinefelter Syndrome (47,XXY):
  • Features: Tall stature, gynecomastia, testicular atrophy (small, firm testes), infertility (azoospermia), learning difficulties.
• Triple X (47,XXX): Often asymptomatic; may have learning difficulties, early menopause.
• XYY Syndrome (47,XYY): Often asymptomatic; may have tall stature, learning difficulties, behavioral issues.

⭐ Barr body (sex chromatin) is absent in Turner Syndrome (45,XO) and present in Klinefelter Syndrome (47,XXY) (one Barr body).

Chromosomal Disorders - Broken & Bent Genes

• Structural Abnormalities:
  • Cri-du-chat syndrome: 5p deletion. Cat-like cry, microcephaly, hypertelorism.
  • DiGeorge/Velocardiofacial syndrome (VCFS): 22q11.2 deletion. 📌 CATCH-22: Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia/Hypoparathyroidism.
• Translocations:
  • Robertsonian: e.g., t(14;21) → Down syndrome risk.
  • Reciprocal: Exchange of segments between non-homologous chromosomes. )
• Diagnostic Techniques:
  • Karyotyping: Gold standard for aneuploidy.
  • FISH: Detects specific microdeletions/duplications.
  • Chromosomal Microarray (CMA): High resolution for copy number variations (CNVs).

• Prenatal Screening & Diagnosis:
  • Screening: NIPT (Non-Invasive Prenatal Testing), Combined Test (NT scan + serum markers).
  • Diagnosis: Amniocentesis, Chorionic Villus Sampling (CVS).

⭐ Chromosomal Microarray (CMA) is often the first-tier genetic test for individuals with unexplained developmental delay, intellectual disability, or multiple congenital anomalies.

High‑Yield Points - ⚡ Biggest Takeaways

• Down syndrome (Trisomy 21): Most common autosomal trisomy; features AVSD, epicanthic folds, intellectual disability.
• Edwards syndrome (Trisomy 18): Presents with clenched fist (overlapping fingers), rocker-bottom feet, severe ID; poor prognosis.
• Patau syndrome (Trisomy 13): Characterized by midline defects (holoprosencephaly, clefts), polydactyly, microphthalmia.
• Turner syndrome (45,X0): Female phenotype with short stature, webbed neck, ovarian dysgenesis, coarctation of aorta.
• Klinefelter syndrome (47,XXY): Male phenotype with tall stature, gynecomastia, hypogonadism (small testes), infertility.
• Cri-du-chat syndrome (5p deletion): Distinctive cat-like cry in infancy, microcephaly, severe intellectual disability.
• DiGeorge syndrome (22q11.2 deletion): CATCH-22 (Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia).