Chromosomal anomalies/Single gene Disorders/Syndromes

Question 1

What are the characteristic features of Noonan Syndrome?

Answer 1

• dysmorphic facies
• short stature
• webbed neck
• lymphatic abnormalities
• skeletal deformities
• bleeding diatheses
• renal diseases
• variable intellectual disabilities
• cardiac anomalies

Question 2

True or false: Noonan syndrome affects more male than female?

Answer 2

FALSE

Equally affects males & females

Question 3

What is the inheritance pattern of Noonan Syndrome?

Answer 3

Most cases are sporadic but can be inherited as an autosomal dominant trait

Question 4

1. What is the name of the group of genetic diseases of which Noonan Syndrome is part of?
2. What are other syndromes included in this group?
3. Why is the group named that way?

Answer 4

1. RASopathies
2. • LEOPARD Syndrome
   • Costello Syndrome
   • Craniofaciocutaneous (CFC) syndrome
3. Disorder of the RAS/mitogen-activated protein kinase (MAPK) pathway

Question 5

What is the gene most commonly mutated in Noonan Syndrome?

Answer 5

• PTPN11 (chromosome locus 12q24.1)

Question 6

What are some other genes known to cause Noonan Syndrome?

Answer 6

• SOS1 **
• KRAS **
• RAF1
• NRAS
• BRAF
• SHOC2

Question 7

What syndrome is also known as the “heart-hand” syndrome?

Answer 7

Holt-Oram Syndrome

Question 8

What are the main extracardiac findings in Holt-Oram Syndrome?

Answer 8

Preaxial radial ray malformations such as

• thumb anomalies (triphalangeal)
• radius aplasia
• phocomelia
• *Skeletal findings can be unilateral or bilateral

Question 9

What are the main extracardiac findings in Alagille Syndrome?

Answer 9

• Biliary anomalies (bile ducts paucity, cholestasis)
• Facial dysmorphism (broad forehead, pointed chin, inverted triangle appearance)
• Cerebral arterial vasculopathy with aneurysms

Question 10

What is the inheritance pattern of Tuberous Sclerosis Complex?

Answer 10

• Autosomal dominant
  BUT
  2/3 of patients have a de novo mutation

Question 11

Which 2 genes are most commonly affected in tuberous sclerosis?

Answer 11

• TSC1
• TSC2
• mutations in the gene TSC1 produce milder sx than mutations in TSC2 gene

Question 12

What are the main features of tuberous sclerosis?

Answer 12

• multisystem hamartomas (brain, cardiac rhabdomyomas, renal angiomyolipoma, facial angiofibroma)
• Epilepsy
• Café-au-lait skin lesions

Question 13

What does a mutation in TSC1 or TSC2 cause?

Answer 13

Affects the proteins hamartin & tuberin –> modulator of mTOR signaling pathway which is important in regulation of cell growth
–>Abnormal coding leads to an increased tumor occurence

Question 14

What is CHARGE syndrome?

Answer 14

C = Coloboma of iris or retina
H = heart defects
A = choanal atresia
R = growth restriction
G = genital anomalies
E = ear anomalies or deafness

• variable clinical spectrum

Question 15

What is the most common affected gene in CHARGE syndrome?

Answer 15

CHD7 gene

Question 16

What is the inheritance pattern of CHARGE syndrome?

Answer 16

Most cases are sporadic (de novo mutation)
BUT
autosomal dominant inheritance & germ-line mosaicism are possible