Kleinefelter, FXS, PWS, Angelman's, Noonan and Williams

Question 1

Kleinefelter Syndrome Ex, PPx?

Answer 1

• Results in extra X chromosome.
• ONLY MALES
• Chief genetic cause - HYPOGONADISM
• 47 chromosomes - extra X chromosome

Question 2

Presentation, Dx and Tx of Kleinefelter syndrome?

Answer 2

1) Infertility
2) Hypogonadism with small testes
3) Gynaecomastia
4) Tall stature
5) Mild learning difficulties

Dx: Chromosome analysis
Tx: Androgen replacement therapy: Testosterone, AND Mastectomy if gynaechomastia.

Question 3

Fragile X syndrome Ex, Ax and PPx?

Answer 3

• X-linked recessive condition (semi-dominant) - MORE COMMON IN MALES.
• Trinucleotide repeat expansion mutation
• FMR1 gene (fragile X mental retardation-1) includes CGG repeat that lengthens as it is passed from generation to generation.
• Once repeat exceeds threshold (>200), no FRAGILE X protein is made and disease results.
• Clinical features in ALL males and half of female carriers.

Question 4

Presentation of Fragile-X?

Answer 4

1) Moderate-severe learning difficulty
2) Delayed motor milestones/speech and language
3) Macrocephaly
4) Long face, LARGE EVERTED EARS, prominent mandible, broad forehead.
5) Macroorchidism (post-puberty)
6) Hyperactivity, emotional and behavioural problems
7) Mitral valve prolapse, autism, scoliosis, joints laxity

Question 5

Dx and Tx of Fragile X?

Answer 5

Dx:

1) Molecular genetic testing of FMR1 gene
2) Prenatal screening possible

Tx: MINOCYCLINE (improvement in general behaviour)

Question 6

Imprinting and Uniparental Disomy:

Answer 6

• Expression of some genes is influenced by the sex of the parent who had transmitted it - Imprinting.
• IN Prader-Willi (hypotonia, developmental delay, hyperphagia, obesity) - chromosome 15 mutation: Paternal copy of this chromosomal region has to function for normal development - if absent child will develop Prader Willi. The failure to inherit maternal copy will result in Angelman syndrome (cognitive impairment, characteristic facial appearance, ataxia and epilepsy).

Question 7

Prader-Willi syndrome PPx and Sx?

Answer 7

• Example of genetic imprinting whereby the phenotype depends on whether the deletion occurs on a gene inherited from the mother or father.
• In PWS the PATERNAL GENE on chromosome 15 is deleted.
• Clinical presentation:
  1) Infancy - hypotonia, poor feeding, genital hypoplasia, delay in motor milestones.
  2) Childhood - hyperplagia (abnormal desire food), progressive obesity, food-seeking behaviour. Short stature and behavioural problems.

Question 8

Angelman’s syndrome PPx and Sx?

Answer 8

• Example of genetic imprinting whereby phenotype depends on whether the deletion occurs on a gene inherited from mother or father.
• IN Angelman’s syndrome - MATERNAL GENE on chromosome 15 is deleted.
• Clinical presentation:
  1) Significant cognitive impairment
  2) Characteristic facial appearance
  3) Developmental delay by 6 months (sit upright/unsupported or make babbling sounds)
  4) Speech impairment with no or minimal use of words
  5) Ataxia and epilepsy
  6) Unique behaviours - combo of laughing and smiling - happy demeanour and excitable personality
  7) Hand flapping common and short attention span

Question 9

Noonan syndrome:

Answer 9

• AUTOSOMAL DOMINANT - Normal karyotype caused by a defect in a gene on chromosome 12. BOTH FEMALES AND MALES.
• Clinical presentation:
  1) Similar to Turner’s - wide space nipples, wobbly neck, short stature
  2) Characteristic: Ptosis, down-slanting eyes, low-set ears.
  3) Congenital heart defects - hypertrophic cardiomyopathy and pulmonary stenosis.
  4) SHORT STATURE
  5) Pectus excavernatum

Question 10

Williams Syndrome:

Answer 10

• Inherited neurodevelopment disorder caused by microdeletion on chromosome 7.
• Clinical presentation:
  1) Short stature
  2) Elfin-like face
  3) Very friendly and social
  4) Learning difficulties
  5) Transient neonatal hypercalcaemia
  6) Congenital heart defect - supravalvular aortic stenosis