neuroblastoma is the most common extracranial solid tumor in childhood and accounts for 7% of malignancies in patients younger than 15 years .
it originates from the sympathetic nervous system , and in particular from a developing and incompletely committed precursor cell derived from neural - crest tissues .
neuroblastoma occurs sporadically in 98% of cases ; a genetic defect is involved in the rare familial neuroblastoma . in the subset of cases of neuroblastoma presenting in the context of other congenital abnormalities of the neural crest , the association with a germline loss - of - function mutation of homeobox gene phox2b has been demonstrated ; on the other hand , familial neuroblastoma not associated with other congenital disorders of the neural crest arises from activating mutations of the anaplastic lymphoma kinase ( alk ) oncogene , whose somatic mutations are , however , observed in sporadic cases of the disease . due to the widespread presence of the sympathetic nervous tissue in various body organs and apparatus ,
the presenting features of neuroblastoma may be variable , depending not only on the location of the primary tumor but also on the frequent metastases .
furthermore , in young children , neuroblastoma exceptionally manifests with paraneoplastic opsoclonus - myoclonus - ataxia ( poma ) due to antineuronal nuclear ( anti - hu ) antibodies   which have also been associated with gastrointestinal disturbances , such as constipation , gut dismotility and paralytic ileus . on the contrary , watery diarrhea due to aberrant vasoactive intestinal peptide secretion
proteinuria is not part of the presenting features of childhood cancer . in patients with neuroblastoma
we report a case where proteinuria was the initial reason for medical evaluation in a child with neuroblastoma .
a 10-month - old girl was admitted to our hospital for investigations for nephrotic - range proteinuria .
she was born to unrelated , italian , healthy parents , by spontaneous delivery at the 38th week of an uncomplicated pregnancy ; her birth weight was 3,110 g. her growth and development were normal until the age of nine months , when she began vomiting , feeding poorly , sweating copiously , and losing weight . on admission ,
her weight was 7,220 g ( < 3th percentile ) , reduced from having previously reached 8,450 g ; her length was 68 cm ; her body temperature was 37.5c with a heart rate of 150 beats / min and respiratory rate of 46 breaths / min ; blood pressure was normal on repeated measurements ( 82/43 mm hg ) .
complete blood cell count showed leukocytes 12,800/mm , red cell count 7,160,000/mm , hemoglobin 15.7 g / dl , platelets 501,000/mm .
blood urea nitrogen was 28 mg / dl ( 10.23 mmol / l ) , creatinine 1.5 mg / dl ( 132.60
mol / l ) , glucose 92 mg / dl ( 5.1 mmol / l ) , ast 25 iu / l , alt 42
iu / l ; total plasma protein level was 7.9 g / dl , with albumin 56.9% ( 4.2 g / dl ) , a1 7.3% , a2 21.3% , 1 6.3% , 2 3.4% ,  4.8% ; uric acid was 8.5 mg / dl , sodium 138 mmol / l , potassium 3.2 mmol / l , chloride 88 mmol / l , venous ph 7.55 with a partial pressure of carbon dioxide of 29.2 mm hg ( probably due to crying and hyperventilation ) , bicarbonate 27.8 mmol / l and be + 4 .
the at iii activity was 100% , prothrombin activity 100% and aptt 29 s , serum lactate dehydrogenase was 376
iu / l and ferritin 5.9 mol / l ( normal value for age 7140 mol / l ) .
she had polyuria and hypostenuria ( diuresis 125 ml / kg/24 h ) ; urinalysis revealed nephrotic - range proteinuria ( 6,100 mg/24 h ) with albuminuria 4,540 mg/24 h , urinary loss of igg 107 mg/24 h , and a1 microglobulin 29.4 mg/24 h ; mild glucosuria ( 39 mg / dl ) and aminoaciduria were also found , without hematuria or casts ; urinary ph was 7.5 and urinary density 1,005 .
electrocardiogram revealed sinus tachycardia 180 beats / min ; echocardiogram showed very mild concentric left ventricular hypertrophy , however , without pathological features .
an endocrinologic evaluation revealed increased plasma renin ( 8 g / l / h ; reference range 1.0 - 4.5 g / l / h ) and aldosterone ( 4.83 nmol / l ; reference range 0.1 - 0.8
nmol / l ) levels , while cortisol and thyroid hormones were within the normal range ; plasma erythropoietin was 42.6 mu / ml ( reference range 3.7 - 37.5 mu / ml ) .
urinary excretion of vanillylmandelic acid was increased to 11 mg/24 h ( 1.57 mg / kg/24 h ; reference range 0.1 - 0.18 mg / kg/24 h ) , while catecholamines were in the normal range , except for the normetanephrine and noradrenaline , which were also elevated ( normetanephrine 1,537 g/24 h , reference range 88 - 440 g/24 h ; noradrenaline 120 g/24 h , reference range 010 g/24 h ) . the ultrasound abdomen examination revealed a solid , suprarenal mass on the left side , sized 2  2 cm ; the right kidney showed slightly increased echogenicity on the upper side .
high - resolution ct showed an abdominal mass sized 5  5.8  10.7 cm , localized between the vertebral bodies d9 and l3 and the aorta , enveloping the celiac tripod , the superior mesenteric artery and bilaterally the renal vessels .
the upper half of the right kidney showed an area of reduced perfusion , while the left kidney showed abnormal tissue density .
adrenal glands were not identifiable in the context of the tumor mass , in which some calcifications were recognizable .
histopathology showed a tumor with a low grade of neuroblastic differentiation , with mitosis - karyorrhexis index ( < 2% ) and elevated mitotic activity .
in this patient , the presenting signs and symptoms of neuroblastoma included severe dehydration , polyglobulia , tubulointerstitial damage with acute kidney injury and renal insufficiency , electrolyte and acid - base unbalancing and heavy glomerular proteinuria .
although diarrhea and dehydration may be observed at presentation of neuroblastoma , tubular alterations are definitely unusual .
we have been able to identify only one case previously : a 4-year - old boy affected by neuroblastoma presenting with nephrotic syndrome has been described in 1979 and renal histology demonstrated membranous glomerulonephritis due to immune complex . on the other hand ,
poma syndrome and gastrointestinal disturbances are associated with anti - hu antibodies , and furthermore , the development of immune complex has been demonstrated in mice with c1300 neuroblastoma tumors confirming the tendency of neuroblastoma to produce immunologic paraneoplastic diseases .
nevertheless , in a recent study performed on a broad series of adults with solid tumors , the prevalence of rheumatic syndromes was only 2.65% , and none of them manifested nephropathy , which shows the exceptionality of those manifestations also in adult patients . in our opinion ,
the physiopathology of the complex clinical picture of the case we describe herein is not ascribable to autoimmune pathogenesis , but rather to a hemodynamic mechanism , subsequently complicated by a series of other physiopathologic phenomena .
the initial event was the development of the tumor mass from the adrenal glands and its extension upwards to envelope the great abdominal blood vessels and bilaterally the renal vessels .
the meaningful feature is that the disruption of renal blood supply and the hemodynamic consequences have been different in the various areas of renal tissue , as revealed by sonography and ct findings .
so , local increased intraglomerular pressure could prime the development of the hyponatremic - hypertensive syndrome , characterized by glomerular hyperfiltration with proteinuria , polyuria , acid - base and electrolyte unbalancing , as rarely described in children with renovascular systemic hypertension [ 9 , 10 , 11 ] .
although in those circumstances , as expected , the consequence of the proteinuria is the development of nephrotic syndrome , in other cases the plasma albumin inexplicably remains at a normal level , even in case of lasting and massive albuminuria , as in our patient [ 11 , 12 , 13 , 14 ] .
we could speculate that the severe dehydration , following copious sweating , vomiting and polyuria , caused such hypovolemia with hemoconcentration that plasma albumin concentration persisted beyond the threshold of edema . also the polyglobulia could be explained by the same mechanism , even if another factor could have been the increased production of erythropoietin , probably stimulated by local renal parenchyma hypoxia .
hypovolemia was also responsible for the mild activation of the renin - angiotensin - aldosterone system and perhaps for metabolic alkalosis with hypochloremia and hypokalemia , but the loss of chloride through sweating was likely the most important cause of this phenomenon .
hypovolemia and the disruption of local renal blood circulation caused acute kidney injury and the signs and symptoms of proximal tubular damage , as glucosuria and aminoaciduria .
on the other hand , the profound hypochloremia was the cause of the metabolic alkalosis , instead of metabolic acidosis typically associated with proximal tubular damage .
increased vasoactive amine secretion from neuroblastoma is not infrequent , and may cause elevated , although usually not severe , hypertension . in conclusion , in our 10-month - old child , alteration of the renal function , at both the glomerular and tubular levels , were the presenting features of neuroblastoma , resulting from multiple pathogenic mechanisms .
our report furthermore emphasizes the high variability and various facets of the clinical manifestations of neuroblastoma .
 neuroblastoma is the most common extracranial solid tumor in childhood . 
 its presenting signs and symptoms may be highly variable , depending on the location of the primary tumor and its local or metastatic diffusion and , rarely , with paraneoplastic syndrome such as opsoclonus - myoclonus - ataxia syndrome and gastrointestinal disturbances , due to autoantibodies or to aberrant secretion of vasoactive intestinal peptide . 
 herein we describe a 10-month - old child with neuroblastoma presenting with a complex clinical picture characterized by acute kidney injury manifested by renal insufficiency and signs and symptoms of tubulointerstitial damage , with polyuria , polydipsia , glucosuria , aminoaciduria and hypochloremic metabolic alkalosis , and of glomerular damage with heavy proteinuria . 
 imaging study documented a suprarenal mass enveloping the aorta and its abdominal and renal ramifications and bilaterally renal veins . 
 this clinical picture shows some analogies with the hyponatremic - hypertensive syndrome concerning the renovascular disease ; however , in absence of systemic arterial hypertension , the heavy proteinuria and the polyuria could be explained by sectional increased intraglomerular pressure , due to local renal blood vessels constriction . 
 hypochloremic metabolic alkalosis probably developed because of local production of renin , responsible of renin - angiotensin - aldosterone system activation , but above all because of chloride loss through sweating . the long lasting dehydration , due to vomiting , sweating and polyuria , caused prolonged prerenal failure evolving in proximal tubular damage manifestations . 
Introduction
Case Report
Discussion