Chromosomal Disorders

Intro & Types - Chromosome Chaos

• Abnormalities in chromosome number or structure.
• Numerical Abnormalities (Aneuploidy & Polyploidy):
  • Aneuploidy: Incorrect chromosome number (not a multiple of haploid set).
    • E.g., Trisomy ($2n+1$), Monosomy ($2n-1$).
    • Mechanism: Nondisjunction (meiosis/mitosis).
  • Polyploidy: >2 haploid sets (e.g., Triploidy $3n$).
• Structural Abnormalities: Altered chromosome structure.
  • Deletions, Duplications.
  • Translocations (Reciprocal, Robertsonian).
  • Inversions (Paracentric, Pericentric).
  • Ring Chromosomes.

⭐ Robertsonian translocations typically involve acrocentric chromosomes (13, 14, 15, 21, 22) and can lead to unbalanced gametes causing conditions like translocation Down syndrome or Patau syndrome carriers.

Autosomal Trisomies - Trisomy Tales

• Down Syndrome (Trisomy 21)

  • Most common viable autosomal trisomy; risk ↑ with maternal age.
  • Features: Intellectual disability, flat facies, upslanting palpebral fissures, epicanthal folds, Brushfield spots (iris), single palmar crease.
  • Associated: Atrioventricular septal defect (AVSD) most common CHD, duodenal atresia, ↑ risk ALL/AML, early-onset Alzheimer's disease.
  • Screening (1st trimester): ↑ Nuchal Translucency (NT), ↓ PAPP-A, ↑ free β-hCG.

• Edwards Syndrome (Trisomy 18) 📌 Election age is 18.

  • Features: Severe intellectual disability, prominent occiput, micrognathia, low-set & malformed ears, clenched fists (overlapping fingers), rocker-bottom feet.
  • Associated: Congenital heart defects (VSD, PDA). Poor prognosis, often fatal within 1st year.

• Patau Syndrome (Trisomy 13) 📌 Puberty around age 13.

  • Features: Severe intellectual disability, microcephaly, holoprosencephaly (midline defects), cleft lip/palate, polydactyly (post-axial), cutis aplasia (scalp defect).
  • Associated: Congenital heart defects. Very poor prognosis, often fatal within days/weeks.

⭐ The most common congenital heart defect in Down syndrome is an Atrioventricular Septal Defect (AVSD).

Sex Chromosome Aneuploidies - X & Y Files

• Klinefelter Syndrome (47,XXY)
  • Male phenotype, tall stature, gynecomastia, small firm testes (hypogonadism), azoospermia, infertility.
  • ↑FSH, ↑LH, ↓testosterone. Barr body (+).
  • Learning difficulties common.
  • 📌 Mnemonic: "Klinefelter's Kings have eXtra X, are Tall, Infertile, with Gynecomastia."
• Turner Syndrome (45,X)
  • Female phenotype, short stature, webbed neck (pterygium colli), shield chest, ovarian dysgenesis (streak ovaries).
  • Primary amenorrhea, infertility. Barr body (-).
  • Associated: Coarctation of aorta (15-20%), bicuspid aortic valve, horseshoe kidney, lymphedema.
  • 📌 Mnemonic: "Tina Turner is Short, has a Webbed neck, and No Xtra X."
• Other Aneuploidies
  • 47,XYY (Jacobs Syndrome): Tall males, normal fertility, often phenotypically normal; may have acne, learning/speech delays.
  • 47,XXX (Triple X Syndrome): Tall females, usually normal development/fertility; ↑risk of learning disabilities, premature ovarian failure.

⭐ Turner Syndrome is the only human monosomy compatible with postnatal life; coarctation of the aorta is a critical cardiovascular association to screen for, present in 15-20% of cases.

Structural Abnormalities - Gene Gymnastics

• Alterations in chromosome structure; can be balanced (no net change in genetic material) or unbalanced (loss/gain of genetic material).
• Key Types & Examples:
  • Deletion: Loss of chromosomal segment.
    • Cri-du-chat syndrome (5p-): High-pitched "cat-like" cry, microcephaly, severe intellectual disability.
    • DiGeorge syndrome (22q11.2 deletion): 📌 CATCH-22 (Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia/Hypoparathyroidism).
  • Duplication: Segment repeated; results in partial trisomy.
  • Translocation: Segment moved to another chromosome or different part of the same chromosome.
    • Reciprocal: Mutual exchange between non-homologous chromosomes (e.g., Philadelphia chromosome).
    • Robertsonian: Fusion of two acrocentric chromosomes (chr 13, 14, 15, 21, 22) at their centromeres; carriers phenotypically normal but risk for unbalanced gametes/offspring.
  • Inversion: Segment breaks off, flips, and reattaches; Paracentric (excludes centromere), Pericentric (includes centromere).
  • Isochromosome: One arm lost, other duplicated, forming a chromosome with two identical arms (e.g., i(Xq) in some Turner syndrome cases).
  • Ring Chromosome: Ends of a chromosome break and fuse, forming a ring; often unstable.

⭐ The Philadelphia chromosome, t(9;22)(q34.1;q11.2), results in the BCR-ABL1 fusion protein and is pathognomonic for Chronic Myeloid Leukemia (CML).

High‑Yield Points - ⚡ Biggest Takeaways

• Down syndrome (Trisomy 21): Most common; intellectual disability, endocardial cushion defects, ↑ risk of Alzheimer's/leukemia.
• Edwards syndrome (Trisomy 18): Rocker-bottom feet, clenched hands, severe ID, poor prognosis.
• Patau syndrome (Trisomy 13): Cleft lip/palate, polydactyly, holoprosencephaly, severe ID.
• Klinefelter syndrome (47,XXY): Male hypogonadism, tall stature, gynecomastia, Barr body present.
• Turner syndrome (45,X): Female hypogonadism, short stature, webbed neck, coarctation of aorta.
• Cri-du-chat (5p deletion): Distinctive cat-like cry, microcephaly, ID.
• DiGeorge syndrome (22q11.2 deletion): CATCH-22 mnemonic; thymic/parathyroid hypoplasia.