Prader-Willi Syndrome (PWS)

Epidemiology and Etiology:

• Possible mechanisms:
• Deletion of 15q11-q13 (paternal) (70%) (same region as AS)
• Critical region may be the HBII-85 snoRNA cluster (reports of translocations, microdeletion)
• Paternally expressed
• Located between SNRPN and UBE3A
• SNRPN may not be required
• UPD 15 (maternal) (25%)
• Disruption of imprinting process (2%)
• Maternal imprinting of paternal chr 15
• May be due to microdeletion of an “imprinting centre” (IC) which overlaps SNRPN promoter
• SNRPN mutation?

Common sites:

Gross features:

• childhood onset obesity
• short stature
• small hands and feet
• hypogonadism

Histologic features:

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

• Deletions:
• FISH for 15q11-q13 microdeletion
• 3 common breakpoints
• 2 common deletions are between BP1 and BP3, or between BP2 and BP3
• Deletion between BP1 and BP2 has been reported (rare)
• LCR (seg-dups) are present at breakpoints
• DNA methylation studies
• Detect virtually all cases

Clinical features:

• severe behaviour problems
• developmental delay and / or mental retardation
• infancy
• Hypotonia
• Poor suck
• FTT
• Childhood-onset obesity
• Hyperphagia
• hypogonadism
• characteristic facies
• small hands and feet
• hypopigmentation
• mental deficiency

References:

• Gersen SL, Keagle MB, eds. Principles of Clinical Cytogenetics (2005).
• ACMG Statement on Diagnostic testing for UPD (2001).
• Sahoo T, del Gaudio D, German JR, et al. Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nat. Genet. 2008;40(6):719-721.
• Thompson & Thompson 2008