Phenotype and course of Hutchinson-Gilford progeria syndrome.
BACKGROUND
Hutchinson-Gilford progeria syndrome is a rare, sporadic, autosomal dominant syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. The genetic basis of most cases of this syndrome is a change from glycine GGC to glycine GGT in codon 608 of the lamin A (LMNA) gene, which activates a cryptic splice donor site to produce abnormal lamin A; this disrupts the nuclear membrane and alters transcription.


METHODS
We enrolled 15 children between 1 and 17 years of age, representing nearly half of the world's known patients with Hutchinson-Gilford progeria syndrome, in a comprehensive clinical protocol between February 2005 and May 2006.


RESULTS
Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented. Previously unrecognized findings included prolonged prothrombin times, elevated platelet counts and serum phosphorus levels, measured reductions in joint range of motion, low-frequency conductive hearing loss, and functional oral deficits. Growth impairment was not related to inadequate nutrition, insulin unresponsiveness, or growth hormone deficiency. Growth hormone treatment in a few patients increased height growth by 10% and weight growth by 50%. Cardiovascular studies revealed diminishing vascular function with age, including elevated blood pressure, reduced vascular compliance, decreased ankle-brachial indexes, and adventitial thickening.


CONCLUSIONS
Establishing the detailed phenotype of Hutchinson-Gilford progeria syndrome is important because advances in understanding this syndrome may offer insight into normal aging. Abnormal lamin A (progerin) appears to accumulate with aging in normal cells. (ClinicalTrials.gov number, NCT00094393.)
Merideth
Melissa A
MA
National Human Genome Research Institute, Intramural Office of Rare Disease, National Institutes of Health, Bethesda, MD 20892-1851, USA.
Gordon
Leslie B
LB
Clauss
Sarah
S
Sachdev
Vandana
V
Smith
Ann C M
AC
Perry
Monique B
MB
Brewer
Carmen C
CC
Zalewski
Christopher
C
Kim
H Jeffrey
HJ
Solomon
Beth
B
Brooks
Brian P
BP
Gerber
Lynn H
LH
Turner
Maria L
ML
Domingo
Demetrio L
DL
Hart
Thomas C
TC
Graf
Jennifer
J
Reynolds
James C
JC
Gropman
Andrea
A
Yanovski
Jack A
JA
Gerhard-Herman
Marie
M
Collins
Francis S
FS
Nabel
Elizabeth G
EG
Cannon
Richard O
RO
Gahl
William A
WA
Introne
Wendy J
WJ
D000293:Adolescent; D001774:Blood Chemical Analysis; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D006128:Growth; D006801:Humans; D007223:Infant; D008297:Male; D010641:Phenotype; D011371:Progeria / Q000097:blood / Q000473:pathology / Q000503:physiopathology*