Genotype-phenotype correlations in Peutz-Jeghers syndrome.
OBJECTIVE
Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder often caused by mutations in STK11. Time to onset of symptoms was characterised for a large collection of individuals with PJS who had been tested for STK11 mutations and genotype-phenotype correlations were evaluated.


METHODS
We characterised mutations in 42 independent probands and also used a historical cohort design to study 51 individuals with Peutz-Jeghers syndrome who had completed self-administered questionnaires.


RESULTS
Mutations were detected in 22/32 (69%) probands with PJS and 0/10 probands referred to rule out PJS. Real-time PCR analysis to quantitate DNA failed to detect any large deletions in PJS participants without STK11 mutations. The median time to onset for gastrointestinal symptoms or polypectomy was 13 years of age but showed a wide variability. Gastric polyps were frequent in PJS participants, with a median age at onset of 16 years. Individuals with missense mutations had a significantly later time to onset of first polypectomy (p = 0.04) and of other symptoms compared with those participants either with truncating mutations or no detectable mutation.


CONCLUSIONS
STK11 mutation analysis should be restricted to individuals who meet PJS criteria or their close relatives. Direct sequencing of STK11 yields a high rate of point mutations in individuals who meet phenotypic PJS criteria. Individuals with missense mutations of STK11 typically had a later time to onset for PJS symptoms. The common occurrence of gastric polyps may facilitate chemopreventive studies for this disorder.
Amos
C I
CI
Department of Epidemiology, U.T. M.D. Anderson Cancer Center HMB, Houston 77030, USA. camos@mdanderson.org
Keitheri-Cheteri
M B
MB
Sabripour
M
M
Wei
C
C
McGarrity
T J
TJ
Seldin
M F
MF
Nations
L
L
Lynch
P M
PM
Fidder
H H
HH
Friedman
E
E
Frazier
M L
ML
D000091162:AMP-Activated Protein Kinase Kinases; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010580:Peutz-Jeghers Syndrome / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics; D040681:Structural Homology, Protein
D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases