1. Turner syndrome: etiology, chromosomal abnormalities, and clinical features
2. Genomic imprinting with one example
3. Applications of karyotyping
4. Klinefelter syndrome: chromosomal abnormalities and clinical features
5. Down syndrome: chromosomal abnormalities and clinical features
6. Six autosomal dominant disorders
7. Six autosomal recessive disorders

• Down syndrome is usually trisomy 21 due to meiotic nondisjunction, with congenital heart defects, intellectual disability, characteristic facies, leukemia risk, and early Alzheimer-type changes.
• Turner syndrome is a sex-chromosome abnormality in females, commonly 45,X, causing short stature, streak ovaries, and webbed neck.
• Klinefelter syndrome, usually 47,XXY, presents in males with testicular atrophy, infertility, tall stature, and gynecomastia.
• Karyotyping detects large numerical and structural chromosomal abnormalities.
• Imprinting is parent-of-origin-specific gene expression, classically illustrated by Prader-Willi and Angelman syndromes.

1. All 5-mark answers
2. All 3-mark answers
3. Turner, Klinefelter, and Down only
4. Everything, one topic at a time

5 MARK QUESTIONS

1. Write the etiology and clinical features of Turner syndrome.

Etiology / chromosomal abnormality

1. Classical type: 45,XO monosomy X, most common.
2. Mosaic type: Two or more cell lines, for example:
   • 45,X/46,XX
   • 45,X/46,XY
   • 45,X/47,XXX
3. Structural abnormalities of X chromosome:
   • Isochromosome of long arm: 46,X,i(Xq)
   • Ring X chromosome: 46,X,r(X)
   • Deletion of short or long arm: del(Xp) or del(Xq)
4. It results from meiotic nondisjunction or loss of an X chromosome during early mitotic divisions.

Clinical features

1. Short stature.
2. Webbed neck with low posterior hairline.
3. Shield-like chest with widely spaced nipples.
4. Lymphedema of hands and feet at birth.
5. Streak ovaries due to gonadal dysgenesis.
6. Primary amenorrhoea, poor development of secondary sexual characters, and infertility.
7. Congenital heart disease, especially coarctation of aorta and bicuspid aortic valve.
8. Renal anomalies, especially horseshoe kidney.
9. Intelligence is usually normal, but visuospatial and learning difficulties may occur.
10. In mosaics containing Y-chromosome material, there is a risk of gonadoblastoma.

2. Describe the clinical features and chromosomal abnormalities of Turner syndrome.

Chromosomal abnormalities

• 45,XO is the classical and commonest form.
• Mosaic forms include 45,X/46,XX and 45,X/46,XY.
• Structural abnormalities include:
  • Isochromosome Xq
  • Ring X chromosome
  • Deletion of Xp or Xq

Clinical features

• Phenotypic female with short stature
• Webbed neck and low hairline
• Shield chest with widely spaced nipples
• Cubitus valgus
• Lymphedema of hands and feet at birth
• Streak ovaries causing primary amenorrhoea and infertility
• Poor secondary sexual development
• Coarctation of aorta and renal anomalies
• Normal intelligence in most cases

3. Write a short note on genomic imprinting and explain with one example.

• One parental allele is selectively silenced by DNA methylation and other epigenetic modifications.
• Therefore, only the maternal or paternal allele is expressed.
• Imprinting marks are established during gametogenesis and are maintained in somatic cells.
• Abnormal imprinting can cause genetic disorders.

Example: Prader-Willi syndrome

• Caused by loss of expression of paternal genes on chromosome 15q11-q13.
• It may occur due to paternal deletion, maternal uniparental disomy, or imprinting defect.
• Clinical features include:
  • Hypotonia in infancy
  • Poor feeding initially
  • Later hyperphagia and obesity
  • Intellectual disability
  • Hypogonadism

4. Enumerate the applications of karyotyping.

Applications

1. Diagnosis of chromosomal disorders such as:
   • Down syndrome
   • Turner syndrome
   • Klinefelter syndrome
2. Detection of numerical abnormalities:
   • Trisomy
   • Monosomy
   • Polyploidy
3. Detection of structural abnormalities:
   • Translocation
   • Deletion
   • Inversion
   • Ring chromosome
   • Isochromosome
4. Prenatal diagnosis using amniotic fluid, chorionic villus, or fetal blood samples.
5. Evaluation of congenital malformations, dysmorphic child, and developmental delay.
6. Evaluation of ambiguous genitalia and disorders of sex development.
7. Evaluation of infertility, recurrent abortions, and stillbirths.
8. Detection of chromosomal abnormalities in malignancies, for example the Philadelphia chromosome in chronic myeloid leukemia.

5. Describe the clinical features and chromosomal abnormalities of Klinefelter syndrome.

Chromosomal abnormalities

• Most common karyotype: 47,XXY.
• Caused by meiotic nondisjunction of sex chromosomes.
• Mosaic forms include:
  • 46,XY/47,XXY
  • Rarely 48,XXXY or 48,XXYY
• Mosaic cases usually have milder manifestations.

Clinical features

1. Tall male with long lower limbs and eunuchoid body habitus.
2. Small, firm, atrophic testes.
3. Hypogonadism with low testosterone level.
4. Sparse facial, pubic, and body hair.
5. Gynecomastia.
6. Infertility due to impaired spermatogenesis or azoospermia.
7. Elevated FSH and LH levels.
8. Mild learning difficulty, especially verbal difficulty, may occur.
9. Increased risk of breast carcinoma, autoimmune diseases, metabolic syndrome, and extragonadal germ-cell tumors.

6. Describe the clinical features and chromosomal abnormalities of Turner syndrome.

Chromosomal abnormalities

• 45,XO
• Mosaic forms: 45,X/46,XX; 45,X/46,XY
• Isochromosome Xq, ring X chromosome, and deletion of X chromosome

Clinical features

• Short stature
• Webbed neck, low posterior hairline
• Shield chest, widely spaced nipples
• Lymphedema at birth
• Streak ovaries
• Primary amenorrhoea and infertility
• Coarctation of aorta
• Horseshoe kidney
• Normal intelligence in most patients

7. Describe the clinical features and chromosomal abnormalities of Down syndrome.

Chromosomal abnormalities

1. Free trisomy 21: 47,XX,+21 or 47,XY,+21
   • About 95% of cases
   • Usually due to meiotic nondisjunction
   • Risk increases with advanced maternal age
2. Robertsonian translocation
   • About 4% of cases
   • Usually translocation of chromosome 21 onto chromosome 14 or 22
   • May be inherited from a phenotypically normal carrier parent
3. Mosaic Down syndrome
   • About 1% of cases
   • Mixture of normal and trisomy 21 cell lines
   • Clinical features are often milder

Clinical features

1. Intellectual disability and developmental delay.
2. Flat facial profile with depressed nasal bridge.
3. Oblique palpebral fissures with epicanthic folds.
4. Protruding tongue and small low-set ears.
5. Hypotonia in infancy.
6. Short stature and short broad hands.
7. Single transverse palmar crease and clinodactyly of fifth finger.
8. Congenital heart disease, especially atrioventricular septal defect.
9. Gastrointestinal anomalies, such as duodenal atresia and Hirschsprung disease.
10. Increased risk of acute leukemia.
11. Recurrent respiratory infections and autoimmune thyroid disease.
12. Early-onset Alzheimer-type changes.

3 MARK QUESTIONS

1. Enlist clinical features of Down syndrome.

• Intellectual disability and developmental delay
• Flat face with depressed nasal bridge
• Oblique palpebral fissures and epicanthic folds
• Hypotonia
• Protruding tongue and small ears
• Single transverse palmar crease
• Clinodactyly of fifth finger
• Congenital heart disease, especially atrioventricular septal defect
• Duodenal atresia or Hirschsprung disease
• Increased risk of leukemia and early Alzheimer disease

2. Enumerate any six autosomal dominant disorders.

1. Marfan syndrome
2. Neurofibromatosis type 1
3. Familial hypercholesterolemia
4. Adult polycystic kidney disease
5. Huntington disease
6. Achondroplasia

3. List any six autosomal recessive disorders.

1. Cystic fibrosis
2. Sickle cell anemia
3. Beta-thalassemia
4. Phenylketonuria
5. Albinism
6. Tay-Sachs disease

4. Describe the clinical features and chromosomal abnormalities of Down syndrome.

Chromosomal abnormality

• 47,XX,+21 or 47,XY,+21 due to meiotic nondisjunction is most common.
• Robertsonian translocation involving chromosome 21 may occur.
• Mosaicism is rare and produces milder features.

Clinical features

• Intellectual disability
• Flat face, epicanthic folds, and upward slanting palpebral fissures
• Hypotonia
• Protruding tongue
• Single transverse palmar crease and clinodactyly
• Congenital heart disease, especially atrioventricular septal defect
• Increased risk of leukemia and early Alzheimer disease