del(17)(p11.2p11.2)

Smith-Magenis Syndrome (SMS)

Hereditary Pressure-Sensitive Neuropathy (HPSN)

Epidemiology and Etiology:

· SMS:

· Common ~3.7 Mb deletion (>90%)

· Some may be larger, with more complicated phenotype

· Proximal to HPSN region

· Resulting from unequal meiotic cross-over at low copy repeats (175-250 kb)

· Sporadic usually

· HPSN:

· Deletion of PMP22

· Peripheral myelin protein 22 gene

· Leads to abnormal myelination of the peripheral nerves

· AKA hereditary neuropathy with liability to pressure palsies (HNPP) and tomaculous neuropathy

· Commonly inherited

· May be de novo

· Can arise maternally:

· By unequal sister chromatid exchange, OR

· By excision of an intrachromatid loop

Common sites:

·

Gross features:

· SMS:

· Distinctive facies

· Multiple congenital anomalies

Histologic features:

·

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

· SMS:

· Common ~3.7 Mb deletion (>90%)

· D17S258 is a marker that is deleted in all SMS cases

· HPSN:

· Deletion of PMP22

· Peripheral myelin protein 22 gene

· Leads to abnormal myelination of the peripheral nerves

Other features:

· SMS:

· Mental defect

· Fractious behavior

· Sleep disturbance (reversal of normal circadian pattern of melatonin secretion)

· Diminished pain sensitivity

· Self-mutilation

· Ex. onychotillomania (pulling out nails)

· HPSN:

· Milder phenotype than the duplication syndrome (CMT)

· Typical is backpacker who complains of numbness and weakness in the arms after a day’s hiking (pressure of shoulder straps)

· Risk of passing on the defect is 50%

· Recurrence risk:

· SMS:

· No known instance of recurrence in a family due to the common deletion

References:

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