Prader-Willi Syndrome

Question 1

What type of genetic syndrome is Prader-Willi?

Answer 1

Disorder of imprinting = Uniparental disomy with deletion of PATERNAL genes

75% microdeletion paternal chromosome 15q11.2-q13
20% maternal uniparental disomy chromosome 15
<5% imprinting centre defect within 15q11.2-q13

Question 2

What is the recurrence risk for Prader Willi?

Answer 2

1%

Question 3

What is the recurrence risk for imprinting center mutation from carrier father?

Answer 3

50%

Question 4

What are the associated medical findings for Prader Willi?

Answer 4

1. Prenatal: hypotonia, decreased fetal movements, abnormal fetal position
2. Infantile: FTT, hypotonia, poor suck
3. Short stature - improve with GH
4. Central obesity and severe hyperphagia
5. Increased diabetes
6. Hypothalamic insufficiency:
   - GH def, increased hypothyroidism
   - abnormal pubertal development
7. Increased central adrenal insufficiency
8. Strabismus, myopia, hyperopia
9. Central and obstructive sleep apnea
10. Enamel hypoplasia, atypical saliva
11. Scoliosis: muscular hypotonia
12. Osteopenia, osteoporosis
13. Increased risk of death with febrile illnesses, esp. pneumonia

Question 5

What are the developmental outcomes for Prader Willi?

Answer 5

1. Motor delays: sitting ~12m, walking ~24m
2. Poor coordination
3. Language delay
4. Mild intellectual disability: average IQ 60-70s, relative weakness in math, sequential processing, short term memory, strength in visual spatial skills, reading
5. Compulsive hyperphagia
6. Typical behavioral phenotype:
   a) tantrums, stubborness, ADHD, manipulative behavior, compulsiveness, rigidity, skin picking
   b) Increased incidence of psychosis
   c) High pain tolerance

Question 6

What is the DDx for Prader Willi syndrome?

Answer 6

1. Several obesity-intellectual disability syndromes incld. Bardet-Biedl Syndrome (polydactyly, retinitis pigmentosa, cystic renal disease), Cohen Syndrome (hypotonia, prominent central incisors, retinal dystrophy), Alstrom Syndrome (cone-rod dystrophy, deafness, type 2 DM)
2. Subset of Fragile X males have early onst obesity

Question 7

What are the health supervision guidelines for Prader-Willi Syndrome?

Answer 7

1. Increased risk of death with febrile illnesses, esp. PNA
2. Heavy involvement by peds endocrinology
3. Growth hormone (through adulthood?)
4. Sleep study and ENT consult prior to GH
5. Aggressive weight management with calorie restriction

Question 8

What are the major clinical manifestations for Prader-Willi syndrome?

Answer 8

1. Infantile hypotonia, poor feeding, FTT
2. Eventual hyperphagia and obesity
3. Hypogonadism
4. Small hands and feet
5. Short stature
6. Low-normal to moderate MR