Sex Chromosome Aneuploidy & Microdeletion syndromes

Question 1

What is the incidence of Klinefelter syndrome?

Answer 1

1 in 500 to 1 in 1000

Question 2

What are the clinical features of Klinefelter syndrome?

Answer 2

• taller than average
• disproportionately long limbs
• 30-50% gynaecomastia (increased risk of breast cancer)
• infertility/Azoospermia
• IQ may be reduced relative to siblings

Question 3

What are the clinical features of 47XYY syndrome?

Answer 3

• Tall with prominent forehead
• IQ may be lower than sibs
• speech delay common
• originally thought to have a strong association with behavioural problems
• normal fertility
• no increased risk of chromosome imbalance in offspring

Question 4

If there are two or more X chromosomes present how many are inactivated?

Answer 4

All but one X will be inactivated

Question 5

What happens to the clinical phenotype as the number of sex chromosomes increases?

Answer 5

The severity increases

Question 6

Where is the SHOX gene located?

Answer 6

Pseudoautosomal region (PAR) of Xp/Yp

Question 7

What clinical phenotype is the SHOX gene associated with?

Answer 7

Short stature

Question 8

What are the differences observed between deletions vs mutations of SHOX?

Answer 8

• Deletions = short stature and skeletal abnormalities in Turner syndrome
• mutations = Leri-Weill dyschondrosteosis (LWD)

Question 9

The characteristic curving of the radius associated with LWD is also known as what?

Answer 9

Madelung deformity

Question 10

LWD arises from heterozygous loss of the SHOX gene. homozygous loss causes a more severe condition - what is it?

Answer 10

Langer mesomelic dysplasia (LMD)

Question 11

What are the two forms of Kallmann syndrome?

Answer 11

1. Autosomal dominant form resulting from loss of function mutations in fibroblast growth factor receptor 1 gene (FGFR1)
2. Sex linked form due to mutation or deletion of the KAL1 gene (close to the PAR)

Question 12

Why is there a higher prevalence of Kallmann syndrome in males?

Answer 12

Because the implicated KAL1 gene partially escapes X inactivation

Question 13

What are the common features of Kallmann syndrome?

Answer 13

• Anosmia (lack of sense of smell) due to agenesis of the olfactory lobes
• hypogonadism secondary to deficiency of hypothalamic gonadotropin-releasing hormone (GnRH)
• mild mental retardation
• colour blindness

Question 14

What are the features of X linked icthyosis?

Answer 14

• generalised scaling of the skin
• large polygonal dark brown scale on extensor aspects of the limbs
• placental steroid sulfatase (STS) deficiency