progeria is a genetic disorder rarely encountered and is characterized by features of premature aging .
it is also known as " hutchinson - gilford progeria syndrome " ( 1 ) .
although signs and symptoms vary in age of onset and severity , they are remarkably consistent overall . children with hgps usually appear normal at birth .
characteristic facies , with receding mandible , narrow nasal bridge and pointed nasal tip develop .
death occurs as a result of complications of severe atherosclerosis , either cardiac disease ( myocardial infarction ) or cerebrovascular disease ( stroke ) , generally between ages 6 and 20 yr .
we report here a 4-yr - old boy with an apparently typical hutchinson - gilford progeria syndrome with g608 g lmna mutation .
a 4-yr - old boy was referred to the department of pediatrics with short stature and sclerodermatous skin on 2 september 2010 .
he was the first child born to non - consanguinous parents with no significant family history .
he was born at full term with birth weight of 3.35 kg by spontaneous virginal delivery .
growth retardation , hair loss , and alteration of skin color on the abdominal region began . on physical examination ,
his length was 88 cm and weight 11.5 kg , both less than 3rd percentile and head circumference was 52 cm ( ca .
1 ) . he had generalized indurated and shiny skin associated with decreased subcutaneous fat , especially on the abdomen .
his hair was fine and sparse and his scalp veins were easily visible ( fig .
his anterior fontanelle was still patent ( horizontal diameter 1.7 cm , vertical diameter 1.4 cm ) .
he had craniofacial disproportion for his age due to micrognatia , prominent eyes , scant eyelashes and small nose .
his bone age was 3 yr . he was neurologically intact with motor and mental development . on serological and hormonal evaluation ,
an echocardiogram did not show concentric left ventricular hypertrophy nor increased left ventricular pressure but showed calcification of aortic and mitral valves ( fig .
2 ) . hypertrophy of internal layer at internal carotid artery suggesting atherosclerosis was found by carotid doppler sonography ( fig .
2 ) . he is on low dose aspirin to prevent thromboembolic episodes and on regular follow up .
we obtained his dna from white blood cell in peripheral blood and sequencing was performed by such method as belows ; samples were extracted using a mg tissue kit .
the pcr reaction was performed with 20 ng of genomic dna as the template in a 30 l reaction mixture by using a ef - taq ( solgent , korea ) as follows : activation of taq polymerase at 95 for 2 min , 35 cycles of 95 for 1 min , 55-63 , and 72 for 1 min each were performed , finishing with a 10 min step at 72. the amplification products were purified with a multiscreen filter plate ( millipore corp . , bedford , ma , usa ) .
the dna samples containing the extension products were added to hi - di formamide ( applied biosystems , foster city , ca ) .
the mixture was incubated at 95 for 5 min , followed by 5 min on ice and then analyzed by abi prism 3730xl dna analyzer ( applied biosystems , foster city , ca , usa ) .
gene study showed typical g608 g ( ggc- > ggt ) point mutation at exon 11 in lmna gene ( fig .
we planned to carry out gene study for her and his family but could n't for their refusal .
after the diagnosis , he regularly visits our clinic for routine lab . , echocardiogram and carotid doppler sonography .
in addition , with our help , he was enrolled in the progeria research foundation ( prf ) in usa and is waiting for farnesyltransferase inhibitors ( ftis ) for clinical trials .
progeria was described for the first time in 1886 , by hutchinson , and ratified by gilford , in 1904 .
it occurs sporadically , with an incidence of 1 in 8 million live births and there are approximately 150 cases described in the medical literature .
it predominates in males with a ratio of 1.5:1 and greater susceptibility of caucasians can be seen in 97% of cases ( 3 ) . in korea ,
this is the first case diagnosed as hutchinson - gilford progeria syndrome by gene study in korea .
there is variability in onset and rate of progression of disease among children , although the final phenotype in these patients is remarkably similar , underscoring the identical common mutation that leads downstream to similar pathobiology ( 10 ) . in this syndrome ,
the average life span is 13 yr ( range 7 - 27 yr ) , but occasionally can survive till the age of 45 yr . the death is mainly due to cardiovascular complications like myocardial infarction or congestive heart failure .
the evidence supports the de novo point mutations in lamin a ( lmna ) gene as the causative factor has been increasing ( 11 ) .
the most common hgps - associated mutation , gly608gly , causes 150 nucleotides encoded in exon 11 to be spliced out of the final mrna and results in a protein that lacks 50 amino acids .
this protein , progerin , retains its c - terminal caax motif but lacks sequences that are required for complete processing and is , therefore , stably farnesylated ( 12 ) .
lamin a is a protein meshwork lining the nucleoplasmic face of the inner nuclear membrane and represents an important determinant of interphase nuclear architecture ( 13 ) .
progerin apparently acts in a dominant - negative manner on the nuclear function of cell types that express lamin a ( 14 ) .
the clinical manifestations are divided into major criteria and signs usually presents itself as follows : the major criteria are a bird - like face ( which occurs around 6 months to one year of age ) , alopecia , prominent veins on the scalp , big eyes , micrognathia , abnormal and slow dentition , pear - shaped chest , short clavicles , bow legs ( coxa valga ) , short upper limbs and prominent articulations , low stature and weight with normal bone age , incomplete sexual maturation , reduction of the adipose tissue and adequate psycho - motor development with normal intelligence .
diagnosis is essentially clinical with major criteria appearing during the first and second years of life ( 15 ) .
cutaneous manifestations are earlier to appear followed by skeletal and cardiovascular systems . in our case , cardiovascular systems showed calcification of aortic and mitral valves and hypertrophy of internal layer at internal carotid artery suggesting atherosclerosis .
skeletal abnormalities include osteolysis , osteoporosis , dystrophic clavicles , coxa valga , " horse riding " stance , thinning of cranial bones , delayed closure of cranial sutures and anterior fontanelle .
prognosis is detrimental to the health of the patient and life expectancy is around 13 yr .
the main mortality factors are cardiovascular diseases ( 75% ) like acute myocardial infarction . despite the advances in cardiovascular surgery ,
the low survival rate remains due to the high capacity of the disease to reproduce the erythematous plaques .
low - dose aspirin is recommended as prophylaxis to prevent atherosclerotic changes ( 15 ) .
a vigorous research effort in the pharmaceutical industry has identified and developed a number of small - molecule compounds that potently and selectively inhibit farnesyltransferase ( ftase ) . in vitro studies in mice
suggest a possible role for the use of farnesyltransferase inhibitors ( ftis ) in progeria ( 15 ) .
farnesylation , a posttranslational modification involving the addition of a 15-carbon isoprene moiety , was implicated as a potential anticancer target when it was discovered that the oncoprotein ras , which has been estimated to be involved in up to 30% of all human cancers , required farnesylation for its function .
two of these drugs ( lonafarnib_sch66336 from schering - plough , kenilworth , nj , and tipifarnib_r115777 from johnson & johnson , new brunswick , nj ) have entered phase iii trials and have been well tolerated , including in trials involving children ( 16 ) .
similar to ras , the lamin a precursor is also farnesylated , with farnesylation serving as a required step to insert prelamin a into the nuclear membrane as well as to allow for the two downstream cleavage steps which complete the processing of lamin a ( 18 ) . for this patient , we are waiting for ftis for clinical trials . with
the knowledge that the single c - to - t base change seen in nearly all cases of hgps created a cryptic splice site and , thus , deleted the normal second endoproteolytic cleavage site in the lamin a processing pathway , it was hypothesized that progerin was forced to retain its farnesyl group and , therefore , could not dissociate itself from the nuclear membrane . with other members of the nuclear lamina
also potentially becoming trapped in complexes with the mislocalized progerin , a mechanistic connection between this permanently farnesylated state and the striking nuclear blebbing and disrupted nuclear architecture seen in hgps cells was proposed , and the possibility of preventing or reversing this phenotype through ftis was raised .
detailed study of hgps and lmna mutations may also advance our understanding of the process of aging .
why do lmna mutant cells enter senescence earlier than normal cells ? ( 19 ) . in summary
, we found a new patient with typical hutchinson - gilford progeria syndrome with mutation of the g608 g in the lmna gene .
this is the first case diagnosed as hutchinson - gilford progeria syndrome by gene study in korea .
 hutchinson - gilford progeria syndrome ( hgps ) is a rare condition originally described by hutchinson in 1886 . 
 death result from cardiac complications in the majority of cases and usually occurs at average age of thirteen years . 
 a 4-yr old boy had typical clinical findings such as short stature , craniofacial disproportion , alopecia , prominent scalp veins and sclerodermatous skin . 
 this abnormal appearance began at age of 1 yr . on serological and hormonal evaluation , all values are within normal range . 
 he was neurologically intact with motor and mental development . 
 an echocardiogram showed calcification of aortic and mitral valves . 
 hypertrophy of internal layer at internal carotid artery suggesting atherosclerosis was found by carotid doppler sonography . 
 he is on low dose aspirin to prevent thromboembolic episodes and on regular follow up . 
 gene study showed typical g608 g ( ggc- > ggt ) point mutation at exon 11 in lmna gene . 
 this is a rare case of hutchinson - gilford progeria syndrome confirmed by genetic analysis in korea . 
INTRODUCTION
CASE DESCRIPTION
DISCUSSION