Imprinting Disorders

Question 1

Chromosomes where imprinting should be considered:

Answer 1

6, 7, 11, 14, 15, 16

Question 2

Russell-Silver/Silver-Russell Syndrome

Answer 2

Mode of imprinting: Maternally imprinted, paternally expressed
Caused by: Can occur due to postzygotic imprinting defects on 11p15.5 (leads to hypomethylation on paternal chromosomes at IC1 affecting genes IGF2 and H19 – REMEMBER THAT THESE GENES ARE DAD’S “MAKE THE BABY BIG AND EVOLUTIONARYILY COMPETITIVE” GENES) or due to MATERNAL UPD 7

Question 3

Russell-Silver: Major Features

Answer 3

Major features:
•Triangular face shape with delicate facial features
•IUGR
•Small for gestational age/low birth weight
•Hypoglycemia
•Excessive sweating, especially at night (may be due to hypoglycemia)
•Developmental delay
•Learning disabilities
•Blue sclera in childhood
•Body asymmetry
•Clinodactyly
•Wide, late-closing fontanelle
•Hypotonia
•GERD
•Lack of subcutaneous fat
•GI complications – constipation
•Precocious puberty

Question 4

Beckwith-Wiedemann Syndrome

Answer 4

Mode of Imprinting: Paternally imprinted, maternally expressed
Critical region: 11p15
Caused by: Paternal UPD, Maternal rearrangements involving 11p15, abnormal methylation of 11p15 (imprinting defect), mutation in maternal CDKN1C
Testing: Methylation studies of 11p15 (loss or gain of methylation at different imprinting centers on the maternal chromosome), UPD cytogenetic studies

Question 5

Beckwith-Wiedemann Syndrome: Major Features

Answer 5

•Overgrowth syndrome
•Macrosomia
•Ear lobe creases, helical ear pits
•Macroglossia (enlarged tongue)
     oMay require surgery
     oMay require speech therapy
•Omphalocele
•Visceromegaly of intra-abdominal organs
•Increased risk for embryonic tumors
      oWilms tumor, hepatoblastoma, neuroblastoma
      oTest for using regular AFP testing (discontinue around age 4, risk drops)
•Renal abnormalities
•Cytomegaly of the fetal adrenal cortex
•Cardiomegaly/Cardiomyopathy

Question 6

Beckwith-Wiedemann Syndrome: Minot Features

Answer 6

Minor features:
•Polyhydramnios
•Neonatal hypoglycemia
•Vascular malformations (facial nevus flammeus)
•Structural heart defects
•Diastasis recti
•Advanced bone age

Question 7

Angelman syndrome

Answer 7

Mode of Imprinting: Paternally imprinted, maternally expressed
Critical region: 15q11.2-q13, UBE3A
Caused by: Paternal UPD, maternally inherited UBE3A mutations, maternal deletions, imprinting defect of maternally inherited chromosome

Question 8

Angelman syndrome: Major Features

Answer 8

Major features:
•“Happy puppet syndrome”
•Delayed attainment of developmental milestones
•Severe developmental delay beginning at 6-12 months
•Limited or absent speech
•Receptive language skills and nonverbal communication skills higher than expressive language skills
•Ataxia
•Laughter and smiling, excitability
•Hand flapping
•Normal head circumference at birth with delayed head growth and microcephaly by age 2
•Seizures
•Abnormal EEG

Question 9

Angelman syndrome: Minor Features

Answer 9

Minor features:
•Dysphagia
•Flat occiput
•Protruding tongue
•Excessive chewing
•Hyperactive deep-tendon reflexes
•Flexed arms during ambulation
•Fascination with water, crinkly items
•Scoliosis
•Constipation

Question 10

Prader Wili syndrome

Answer 10

Mode of Imprinting: Maternally imprinted, Paternally expressed
Critical region: 15q11.2-q13
Caused by: Maternal UPD, paternal deletion

Question 11

Prader Wili syndrome: Features

Answer 11

•Hypotonia and failure to thrive in neonatal/early development
•Global developmental delay
•Excessive eating (including eating non-food items)
•Obesity
•Mild intellectual disability
•Hypogonadism
•Hypothyroidism
•Sleep abnormalities
•Behavioral problems
   oAutistic behavior
   oControlling/manupilative behavior
   oTantrums
   oHyperactivity
   oPsychosis
   oCompulsive behavior