Imprinting Flashcards
What are the neonatal features of Prader-Willi syndrome?
Neonatal features:
Congenital hypotonia
Feeding problems/FTT
Narrow bifrontal diameter
Almond-shaped eyes
Down-turned mouth
Small hands/feet
What are the childhood/adult features of Prader-Willi syndrome?
Childhood/Adult features:
Hyperphagia, obesity
Developmental delay
Behavior problems
Sleep disorder
Short stature
Hypogonadism
What is the phenotype of Angelman syndrome?
Developmental delay/absent speech
Microcephaly, brachycephaly, broad jaw
Frequent laughter, happy demeanor
Seizures with specific EEG pattern
Ataxic (jerky) movements of the limbs and trunk
What causes Uniparental Disomy in PWS/AS?
Trisomy rescue
Two paternal chr15 in Angelman
Two maternal chr15 in PWS
Deletion of the active paternal chromosome 15q11-13 occurs in what percentage in what disorder?
70% of PWS
Maternal uniparental disomy (UPD) of chromosome 15q11-13 occurs in what percentage in what disorder?
~29% of PWS
Imprinting mutations occur in what percent of PWS?
Some say 1%/some say 5%
Deletion of the active maternal chromosome 15q11-13 occurs in what percentage in what disorder?
68% of Angelman
Paternal uniparental disomy (UPD) of chromosome 15q11-13 occurs in what percentage in what disorder?
7% of Angelman
UBE3A mutations occur in what percentage of Angelman syndrome?
11% of cases
Imprinting mutations occur in what percent of Angelman syndrome?
< 0.3% of cases
What is the phenotype of Silver-Russell syndrome?
Prenatal-onset growth retardation, short stature, triangular face, blue sclerae, café au lait spots, limb asymmetry, hypoglycemia
What causes Silver-Russell syndrome?
Abnormal imprinting of 11p15.5, chr 7
Hypomethylation of the imprinted control region 1 (ICR1) at 11p15.5 causes SRS in 35%-50%
Maternal uniparental disomy (mUPD7) causes SRS in 7%-10% of individuals.
There are a small number of individuals with SRS who have duplications, deletions or translocations involving the imprinting centers at 11p15.5 or duplications, deletions, or translocations involving chromosome 7
Rarely, affected individuals with pathogenic variants in CDKN1C, IGF2, PLAG1, and HMGA2 have been described.
In Angelman syndrome which mechanism can be inherited and warrant parental testing?
Imprinting center deletions, 15q deletions and UBE3A gene variants
Only one activeUBE3Aalleleis required for normal brain functioning and it has to be mother’s copy. Inheriting from father will not cause AS. Family history may skip multiple generations for AS symptoms.
If your patient with known PWS diagnosis and abnormal methylation has a sibling with PWS features, what is the chance this sibling will also have abnormal methylation?
If sibling clinically has PWS, there is a 50% chance.
Suspect father has an PWS IC deletion in his maternal allele (known to occur in ~5% cases).
What testing do you order in Russell-Silver syndrome?
Methylation analysis of 11p15.5 ICR1/ICR2 and maternal UPD7 studies may be ordered simultaneously.
Ifmethylation analysisof 11p15.5 ICR1/ICR2 and maternal UPD7 studies are normal,sequence analysisofIGF2,CDKN1C,PLAG1, andHMGA2may be considered.
What percentage of Russell-Silver syndrome have non-diagnostic lab studies?
40%
What are the management recommendations in Beckwith Weideman syndrome?
Monitor for hypoglycemia, especially in the neonatal period;
Screen for embryonal tumors by abdominal ultrasound examination every three months until age eight years;
Monitor serum alpha-fetoprotein (AFP) concentration every two to three months in the first four years of life for early detection of hepatoblastoma;
Annual renal ultrasound examination for affected individuals between age eight years and mid-adolescence to identify those with nephrocalcinosis or medullary sponge kidney disease;
Consideration of annual or biannual measurement of urinary calcium/creatinine ratio.
