noonan syndrome is characterized by facial dysmorphology ( low set of ears , hypertelorism , downward eyeslant and epicathic fold ) , growth failure and congenital heart anomalies such as pulmonary stenosis and atrial septum defects ( 1 ) . lymphedema with noonan syndrome reportedly occurs in the neonatal and later period ( 2 , 3 ) . although protein - losing enteropathy ( ple ) occurs in post - cardiac operations , such as the fontan operation , inflammatory bowel syndrome , connective tissue diseases and parasitic disease ( 4,5,6,7,8,9 ) , ple with noonan syndrome is rarely reported ( 10 ) . we treated a 13-yr - old boy with noonan syndrome accompanied by late - onset lymphedema , hydrocele testis and ple during growth hormone treatment for growth failure . a 13-yr - old boy with prior diagnosis of noonan syndrome based on characteristic facial deformation and congenital heart anomaly ( pulmonary stenosis and atrial septum defect ) came to our hospital complaining of edema of his leg in september 2007 . he had no tenderness on his abdomen and legs and was diagnosed as having lymphedema . his height was 132.5 cm ( 3.6 sd ) and his weight was 27.6 kg ( 2.2 sd ) . his weight had increased by 1.4 kg within 1 wk before coming to the hospital . no polyuria or oliguria was observed . before coming to our hospital , he practiced hard for athletic meets and stood for long periods of time each day . edema of the lower abdomen and hydrocele testis were observed . in regard to his past history , neuroblastoma was suspected at 6 mo of age because the level of urinary vanillylmandelic acid ( u - vma ) was high , although mri and ri testing identified no tumor . an operation for pulmonary stenosis and atrial septum defect was conducted at 6 yr of age . for his short stature , growth hormone treatment was started at the age of 12 yr of age .. at 12 yr of age ( height , 124.7 cm , 3.21 sd ; weight , 22.1 kg , 2.1 sd ) , he was diagnosed as having growth hormone deficiency ( igf-1 , 158 ng / ml ; peak value of serum growth hormone after provocation ; insulin , 5.3 ng / ml ; clonidine , 5.2 ng / ml ) . growth hormone treatment was started after informed consent was obtained from his parents . his endocrinological data at start of growth hormone treatment was as follows : tsh , 4.68 u / ml ; free t4 , 1.23 ng / dl ; fsh , 22.1 miu / ml ; lh , 1.5 miu / ml ; and testosterone , 13.9 ng / ml . his testicular volume reached the pubertal level soon after starting growth hormone treatment . his amount of food intake and food preference were not altered before and after start of growth hormone treatment . during growth hormone treatment , asymptomatic hypoproteinemia hypoproteinemia worsen after athletic meets in 2006 and 2007 . ) . without specific therapy , he was admitted to our hospital for examination of the cause of lymphedema and hypoproteinemia . laboratory testing on admission ( table 1table 1  results of laboratory testing at admission ) showed hypoproteinemia , hypoalbuminemia and hypoimmunoglobulinemia . no hypereosinophilia reflecting parasitic diseases or eosinophilic gastroenteropathy was found . the level of serum neuron - specific enolase ( nse ) and u - vma were within the normal ranges . echocardiography showed that his cardiac function was normal and that he did not have right ventricular failure or constrictive pericarditis . soon after admission , 2.5 g of albumin was injected into him ; he was made to rest in bed and to raise his legs to maintain his blood pressure ( fig . growth hormone treatment was stopped because of its fluid retention effects . on day 2 , 99mtc - human serum albumin ( hsa ) scintigraphy on showed protein loss from the small intestine at 6 h ( figs . 5 results of 99mtc - human serum albumin scintigraphy on day 2 ( a , 5 min after injection ; b , 6 h after injection ) and day 6 ( c , 5 min after injection ; d , 8 h after injection ) . white arrows indicate protein loss from the small intestine . ) . because his level of 1 anti - trypsin clearance on day 5 was elevated ( 56.1 ml / d ) , he was diagnosed as having ple .   clinical courses during and around admission . results of 99mtc - human serum albumin scintigraphy on day 2 ( a , 5 min after injection ; b , 6 h after injection ) and day 6 ( c , 5 min after injection ; d , 8 h after injection ) . his serum total protein and albumin levels increased each day after admission . on day 6 , his level of 1 anti - trypsin clearance on day 13 was normal ( 10.8 ml / d ) . although he was allowed to start walking on day 14 and growth hormone treatment was restarted on day 19 , his serum total protein and albumin levels continued to rise . his level of 1 anti - trypsin clearance did not elevate again ( day 18 ; 6.1 ml / d , day 23 ; 3.9 ml / d ) . disorder of lymph vessel formation is frequently reported with noonan syndrome ( 11 , 12 ) . although lymphedema secondary to disorder of lymph vessel formation is reported in up to 20% of noonan syndrome patients ( 3 ) , ple is rarely reported with noonan syndrome ( 10 ) . recent reports showed that growth hormone treatment does not increase any severe adverse event in noonan syndrome ( 13 , 14 ) . our patient also showed asymptomatic hypoproteinemia and hypoalbuminemia after athletic meet in the year prior to admission ( fig . 3 ) . although growth hormone treatment had not been discontinued , hypoproteinemia and hypoalbuminemia have not continued . therefore , growth hormone treatment does not seem to be the main trigger of his lymphedema and ple . although a fat - rich , low - protein diet aggravates ple , our patient did not prefer this kind of food . alteration of the amount of food intake or food preference was not observed after start of growth hormone therapy . he received no specific therapy for ple , such as protein - rich , low - fat diet therapy , during admission , and the amount and composition of his food intake were not altered before and after admission . so , in this case , food was considered to have had little effect on the occurrence of ple . lymphedema and ple that accompany constrictive pericarditis or that occur after cardiovascular surgery , such as the fontan operation , are commonly reported ( 4 , 5 ) . although our patient also underwent a cardiac operation for atrial septum defect and pulmonary stenosis , an echocardiogram did not indicate right ventricular failure or constrictive pericarditis before or after start of the growth hormone treatment . recent reports show that growth hormone treatment does not increase adverse effects on cardiac muscle mass in noonan syndrome ( 15 , 16 ) . therefore , operation and cardiac disorders are also not presumed to have caused his lymphedema and ple in this patient . no tumors , such as neuroblastoma and lymphoma , that occasionally cause ple ( 17 , 18 ) were found in the present patient . our patient practiced hard for athletic meets and stood for long periods of time each day before coming to our hospital ( fig . 3 ) . standing for long periods of time congested the lymph stream and increased the pressure in lymph vessels . although lymphangiography and lymphoscintigraphy were not conducted on this patient , dysplasia and hypoplasia of lymph vessels originating from noonan syndrome might have contributed to congestion of the lymph stream . these were considered to cause defluxion of lymph into interstitial tissues of the legs , lower abdomen and intestine , which caused lymphedema and ple . recently , genetic mutations in the genes organizing the ras - erk mapk pathway were found to be causative candidates of noonan syndrome ( 19,20,21,22 ) . the mapk pathway is activated by vegfr3 , an important component for lymphangiogenesis ( 23 ) . although the genotype - phenotype correlation is not fully understood in noonan syndrome , the severity of disorder in lymph vessel formation might differ according to the genetic mutation . in addition , the severity of the disorder in lymph vessel formation might engender different clinical symptoms of noonan syndrome : asymptomatic or lymph edema only or both lymphedema and ple , as well as early onset or late onset . in conclusion , asymptomatic hypoproteinemia attributable to ple , as our patient showed , might be more common in patients with noonan syndrome than previously thought . therefore , more attentions to the clinical symptoms such as lymphedema and hydrocele testis , and the serum levels of total protein and albumin should be paid in patients with noonan syndrome .
noonan syndrome is characterized by facial dysmorphology , congenital heart disease and growth failure . although it is also accompanied by deranged lymph - vessel formation , protein - losing enteropathy ( ple ) with noonan syndrome is rarely reported . 
 we report clinical information about a boy with noonan syndrome and late - onset lymphedema and ple after standing for long periods of time during athletic practice sessions . 
 the boy recovered from lymphedema and ple after administration of 2.5 g of albumin followed by resting and raising his legs . 
 they did not recur after he began walking again . standing for long periods of time congested the lymph stream at the abdominal lymph vessel 
 , whose formation is frequently disturbed in noonan syndrome , and the increased pressure caused lymphedema and ple . 
 ple is one of the clinical manifestations of noonan syndrome .