del(4)(p16.3)

Wolf-Hirschhorn Syndrome (WHS)

Pitt-Rogers-Danks Syndrome

Epidemiology and Etiology:

· De novo deletion (75%)

· “pure deletion” with no other abnormality

· Unbalanced translocation inherited from parental balanced rearrangement (13%)

· Ring 4

· 4p- mosaicism

Common sites:

·

Gross features:

· Distinctive facies

· “Greek warrior helmet appearance” of the nose

· Microcephaly

· Prominent glabella

· Highly-arched eyebrows

· Poorly-formed ears

· Conductive hearing loss (>40%)

· Pits / tags

· Others

· IUGR

· Post-natal growth retardation

· Muscle underdevelopment

· Skeletal abnormalities (60-70%)

· Congenital heart defects (~50%)

· Urinary tract malformations (25%)

· Structural brain abnormalities (33%)

Histologic features:

·

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

· G-banding will recognize ~60-70%

· FISH will detect >95%

· Wolf-Hirschhorn critical region (WHCR) (4p16.3)

· 165 kb region near the telomere

· 2 genes: WHSC1 and WHSC2

· LETM1 distal to this may also play a role in the phenotype

· Neuromuscular effects

· classical deletion

· ~500 kb deletion within 4p16.3

· Severity correlates with the extent of the deletion

· A separate phenotype is seen with more proximal deletions

Other features:

· Can be confidently recognized clinically

· Two “forms”

· Severe classical

· Relatively mild

· Developmental delay / mental retardation of variable degree (all)

· Seizures (50-100%)

· Pitt-Rogers-Danks syndrome is less severe phenotypic version of Wolf-Hirschhorn syndrome

· The same deletion may cause either syndrome

References:

· Gardner RJM, Sutherland GR. Chromosome Abnormalities and Genetic Counseling. 2nd ed. Oxford University Press, USA; 1996.