Non-linkage of familial rhabdoid tumors to SMARCB1 implies a second locus for the rhabdoid tumor predisposition syndrome

BACKGROUND: Rhabdoid tumors represent an independent entity among embryonal neoplasms. These tumors affect the kidney (RTK, rhabdoid tumor of kidney) and central nervous system (AT/RT, atypical teratoid, rhabdoid tumor), but may also be found in peripheral soft tissue. Unifying features include immunohistochemical characteristics and inactivation of the putative tumor suppressor gene SMARCB1 (hSNF5/INI1) in chromosome 22q11.2. Several familial cases have been published and summarized under the term rhabdoid tumor predisposition syndrome. In all of the published familial cases, inactivation of SMARCB1 was detected in tumor tissues. PROCEDURE AND RESULTS: We report on a family with three children, two of which were affected by rhabdoid tumors, one RTK, the other an AT/RT. While both children demonstrated typical morphological and clinical features neither the RTK nor the AT/RT showed evidence for inactivation of SMARCB1 in molecular studies including CGH and array CGH, FISH, gene dosage analysis by dHPLC, and DNA-sequencing. Immunohistochemistry for SMARCB1 showed normal expression within the nuclei of tumor cells. Furthermore, both children inherited different paternal and maternal SMARCB1 alleles evidenced by haplotype analysis. Conventional cytogenetic, FISH, and mutation analyses lacked evidence for SMARCB1 aberrations or gross chromosomal changes in the parents. CONCLUSIONS: We thus demonstrate a family with rhabdoid tumor predisposition syndrome without linkage to SMARCB1. This finding indicates that other loci than SMARCB1 below the resolution of array CGH are involved in the origin of these tumors. Our data impact on the clinical counseling of affected families and warrant further studies in the molecular biology of these enigmatic tumors.     

Management of pediatric renal tumor: Past and future trials of the Japan Wilms Tumor Study Group

The Japan Wilms Tumor Study group (JWiTS) was founded in 1996 to improve outcomes for children with renal tumor in Japan, and a nationwide multicenter cooperative study was initiated thereafter. JWiTS‐1 (1996–2005) was analyzed, and JWiTS‐2 (2005–2014) is now under analysis; the following problems have been identified and used to decide future study protocol: (i) there has been a decline in survival rate for patients with rhabdoid tumor of the kidney (RTK) and new treatment strategies are required; (ii) the survival rate for bilateral Wilms tumors (BWT) has improved, but results for renal preservation are unsatisfactory; (iii) the prognosis of stage IV favorable nephroblastoma is very good, suggesting that the current protocols provide overtreatment, particularly for patients with lung metastasis; and (iv) no effective biological risk factors exist for predicting the outcome of Wilms tumor, and a study of the genetic changes of these tumors is necessary to determine biological markers for use in risk classification. To solve these issues, the development of a new risk classification of pediatric renal tumors is required. In addition, different study protocols should be developed according to the risk‐based classification of the patients. Further, a new study protocol for BWT began in 2015, and new study protocols are being prepared for RTK, and for Wilms tumor with lung metastasis. In addition, an analysis of biological markers with regard to risk classification is to be performed. Furthermore, to create new protocols for patients with rare renal tumors, international collaboration with Children's Oncology Group and International Society of Pediatric Oncology is necessary.     

Teratoid Wilms' tumor, an important variant of nephroblastoma

PurposeThe teratoid histologic variant of Wilms’ tumor is rare, with only 15 prior reported cases. We review these and report an additional case in which a cytogenetic abnormality was identified that has not previously been reported in a teratoid Wilms’ tumor.Materials and methodsA medline search revealed 15 previously reported cases of the teratoid variant of Wilms’ tumor. We summarized the characteristics of these cases with attention to radiologic appearance, stage, laterality, histology, response to chemotherapy and outcomes.ResultsCharacteristic radiologic features suggesting teratoid Wilms’ tumor were calcific densities and stippling, or areas of attenuation indicating adipose tissue. The majority of teratoid Wilms’ tumor patients had a high tumor stage at presentation (50% stage III or greater). The incidence of bilateral tumors was 38%. Chemotherapy was administered in nine cases and in only one (11%) was there a cytoreductive response. Four deaths (25%) occurred amongst these patients.ConclusionsTeratoid Wilms’ tumors appear to present with a high stage, increased incidence of bilaterality and have a high mortality rate. Treatment strategies should focus on total surgical extirpation, including metastatic sites when feasible, due to this entity's limited response to chemotherapy.     

Results of the SIOP 93-01/GPOH trial and study for the treatment of patients with unilateral nonmetastatic Wilms Tumor

BACKGROUND: The treatment of Wilms Tumor is integrated into clinical trials since the 1970's. In contrast to the National Wilms Tumor Study Group (NWTSG) the SIOP trials and studies largely focus on the issue of preoperative therapy to facilitate surgery of a shrunken tumor and to treat metastasis as early as possible. PATIENTS AND METHODS: In the SIOP 93-01/GPOH trial and study 1 020 patients with a newly diagnosed renal tumor were registered. 847 of them had a histological proven Wilms Tumor, of whom 637 were unilateral localized, and 173 tumors had an other histology [40 congenital mesoblastic nephroma (CMN), 51 clear cell sarcoma (CCSK), 24 rhabdoid tumor (RTK) and 58 other tumors]. Preoperative chemotherapy in benign tumors was given to 1.3 % of the patients. The main objective of the trial was the randomized question, if the postoperative two drug chemotherapy for stage I in intermediate risk or anaplasia can be reduced from conventional 3 courses to an experimental 1 course without loss of efficacy. RESULTS: 519 patients with unilateral nonmetastatic Wilms did receive preoperative chemotherapy. The histology in this group of patients was of intermediate risk in 469 (90 %) patients, 14 (3 %) tumors were low risk and 36 (7 %) high risk. The stage distribution of the tumors was stage I in 315 (61 %), stage II N- in 126 (24 %), stage II N+ in 25 (5 %) and stage III in 36 (7 %) patients. In 17 (3 %) patients the tumor stage remained unclear. Tumor volume was measured in 487 patients before and in 402 after preoperative chemotherapy. The median tumor volume did shrink from 353 to 126 ml. The amount of volume reduction depends on the histological subtype. The event free survival (EFS) after 5 years was 91 % for all patients with unilateral Wilms tumor without distant metastasis. Randomisation was done in 43.7 % for stage I patients and there was no difference in EFS for both treatment arms (90 versus 91 %). The EFS is identical for patients with stage I and II N- (0.92), as well as for stage II N+ and III (0.82). The tumor volume after chemotherapy is a prognostic factor for intermediate risk tumors with the exception of epithelial and stromal predominant tumors. These two subtypes often present as large tumors, they do not shrink during preoperative chemotherapy but they still have an excellent prognosis. On the other hand the prognosis of patients with blastemal predominant subtype after preoperative chemotherapy is worse than in any other patient group of intermediate risk tumors. There are less blastemal predominant tumors compared to primary surgery, but they are chemotherapeutic resistant selected by the preoperative chemotherapy. CONCLUSION: Patients with unilateral Wilms tumor without metastasis have an excellent prognosis. The post-operative chemotherapy in stage I can be reduced to 4 weeks without worsening treatment outcome. The reduction of the tumor volume could be identified as a helpful marker for stratification of post-operative treatment. Post-chemotherapy blastemal predominant subtype of Wilms tumor has to be classified as high risk tumor. Focal anaplasia has a better prognosis than diffuse anaplasia and will be classified as intermediate risk tumor.     

Rhabdoid Tumor of the Kidney Is a Component of the Rhabdoid Predisposition Syndrome

The rhabdoid predisposition syndrome (RPS) is characterized by pedigrees in which two or more individuals carry germline mutations of the hSNF5/INI1 tumor suppressor gene. The tumors associated with the syndrome include atypical teratoid/rhabdoid tumor (AT/RT), choroid plexus carcinoma, medulloblastoma, and extrarenal rhabdoid tumor. Rhabdoid tumor of the kidney (RTK) has not been described as part of the RPS. We report a case of a 7-month-old boy with RTK whose sister had a malignant cerebellar tumor followed by a malignant lung and pleural tumor of childhood with typical rhabdoid histology. Molecular genetic analysis of the RTK and tissue from the pleural tumor revealed in both cases identical nonsense mutations of the hSNF5/INI1 gene on chromosome 22q11.2, where thymidine was substituted for cytosine in base 472. The proband had an identical germline mutation. This is the fifth genetically analyzed RPS pedigree and the first to include an RTK.     

The clinical significance of asymptomatic gross and microscopic hematuria in children

BACKGROUND: The development of asymptomatic gross or microscopic hematuria is relatively common in children. OBJECTIVE: To evaluate the clinical importance of hematuria in children and the necessity for such an evaluation using a defined diagnostic protocol. DESIGN: The protocol included a personal and family history, physical examination and blood pressure determination, and a set of comprehensive laboratory and radiological examinations. RESULTS: Of 342 children with microscopic hematuria, no cause was uncovered in 274 patients. The most common cause discovered was hypercalciuria (16%), followed by post-streptococcal glomerulonephritis (1%). Of 228 children with gross hematuria, no cause was uncovered in 86 patients. The most common cause discovered was hypercalciuria (22%). Ten patients had clinically important structural abnormalities. Fifty-three patients qualified for renal biopsy; 36 had IgA nephropathy. CONCLUSIONS: Our results suggest that diagnostic evaluation for potential causes of asymptomatic microscopic hematuria in children may not be necessary. Because microscopic hematuria can, rarely, be the first sign of occult renal disease, long-term follow-up is mandatory. As clinically important abnormalities of the urinary tract are commonly discovered in children with asymptomatic gross hematuria, a thorough diagnostic evaluation is warranted.     

Outcome of pediatric renal tumor treated using the Japan Wilms Tumor Study-1 (JWiTS-1) protocol: a report from the JWiTS Group

Purpose

In 1996, the Japan Wilms Tumor Study (JWiTS) group was founded to elucidate the efficacy and safety of the regimen established by the National Wilms Tumor Study (NWTS) group in the USA, and a multicenter cooperative study (JWiTS-1) was started in Japan. This report reviews the results of JWiTS-1.

Methods

A total of 307 patients with malignant renal tumor were enrolled in the JWiTS-1 study between 1996 and 2005. Central pathological diagnosis and follow-up data were available in 210 cases. The protocol regimens were similar to the NWTS-5 regimens. Clinical stage was classified according to the Japanese Staging System.

Results

Five-year overall survival (OS) rate was 91.1% for nephroblastoma, 72.9% for clear cell sarcoma of the kidney (CCSK), and 22.2% for rhabdoid tumor of the kidney (RTK). In the nephroblastoma patients, 5-year OS was 90.5% for stage I disease, 92.2% for stage II, 90.9% for stage III, 86.7% for stage IV, and 78.7% for stage V.

Conclusions

The OS of patients in the JWiTS-1 study were comparable with the results of other multicenter studies in the USA and Europe. The outcome for patients with nephroblastoma and CCSK was fair. In contrast, the cure rate for those with RTK was not satisfactory. New treatment strategies are needed for patients with RTK.     

Rhabdoid tumor of the kidney: A report of two cases with respective tumor markers and a specific chromosomal abnormality,del(11p13)

Malignant rhabdoid tumor is a rare, aggressive, invariably lethal tumor that is resistant to multimodal treatment. In this report, two patients with malignant rhabdoid tumor of the kidney (RTK) are described. The first patient is the first case of RTK with hyperreninemia, and the second case is also the first case with a specific chromosomal abnormality, del 11p13. The first patient presented with hematuria and a mass in the left kidney. Plasma renin, angiotensin, and aldosterone levels were elevated and paralleled the tumor progression. The karyotype of the tumor cells was normal (46, XX). In the second patient, who presented with a mass in the right kidney, the concentration of plasma tissue polypeptide antigen was elevated and paralleled the tumor progression. The karyotype of the tumor cells was 46, XX, del(11)(pter-p13::p12-qter). RTK with a cytogenetic abnormality of del(11p13), which is usually found in aniridia-Wilms' tumor syndrome, has not been known. Both patients died of metastatic disease within 7 months of diagnosis in spite of the multi-modal therapy. The clinicopathology of RTK and the differences between Wilms' tumor and RTK raise compelling questions which should be the subject of future studies. © 1996 Wiley-Liss, Inc.     

Wilms’ Tumor: A 24-year Retrospective Study from a Single Center

Medical records of 71 children with Wilms’ tumor at Sisli Etfal Education and Research Hospital between 1990 and 2014 were reviewed. Mean age at diagnosis was 3.11 years (2 days–7 years). Male to female ratio was M/F = 6/10. The incidence of associated anomaly was 16.9%. Clinical manifestations included abdominal mass (89%), hematuria (30%), hypertansion (25%), abdominal pain (15%), fever (5%), restlessness (2%), weight loss (2%), varicocele (1%). Ultrasound (USG) was the most often initial study in a child presenting with abdominal mass. Doppler USG was also made to evaluate the inferior vena cava (IVC) for the presence of tumor extension in children with renal mass. The left kidney was affected in 33 patients (46.5%), the right was affected in 31 patients (43.7%). Two patients was extrarenal (2.8%). And 5 patients (7.04%) were bilateral on the presentation. Preoperative chemotheraphy was done in 14 cases. In 63 patients with unilateral Wilm tm, unilateral radical nefrectomy is performed. In one patient with solitary kidney, nephron sparing surgery (NSS) is performed. In 3 patients with bilateral tm NSS is performed and in 2 patients with bilateral Wilms’ tm NSS is performed in one side and nefrectomy on the other side. Out of 71 Wilms tumor (WT) patients, 17 of them has been out of our follow. And 4 of them are died. Ten of them has metastases. Forty children are under follow with no metastases. Patients with WT needs a multimodal, multidisiplinary treatment with the cooperation of pediatric oncologist and pediatric surgeon and needs close follow-up.     

Pretreatment, ultrasound-guided cutting needle biopsies in childhood renal tumors

BACKGROUND: The current International Society of Paediatric Oncology (SIOP)-10 protocol does not allow pretreatment histological classification of low-stage renal tumors in children for fear of needle tract recurrences. The aims of this retrospective study were to evaluate the safety, sensitivity, and specificity of ultrasound-guided cutting needle biopsies (UCNB) performed at our institution in pediatric patients with renal tumors. PROCEDURE: Of 28 pediatric patients presenting with a renal tumor between 1988 and 1996, 25 underwent biopsy with the Biopty biopsy instrument (needle diameter 1.2 mm). The preoperative biopsy and nephrectomy slides were reviewed by a SIOP reference pathologist. The patients' hospital records were reviewed and biopsy complications were noted. RESULTS: At review of the nephrectomy slides, the diagnoses were: Wilms tumor (16 patients), with anaplasia in one case, rhabdoid tumor (2 patients), neuroblastoma (2 patients), mesoblastic nephroma (2 patients), clear cell sarcoma (1 patient), malignant teratoma (1 patient), and renal cell carcinoma (1 patient). No needle tract recurrence or other major complication was observed. The only complication was local pain at the biopsy site, which occurred in 24% (6/25) of the cases. The sensitivity of UCNB was 76% (19/25); five biopsies did not yield diagnostic material and one was not concordant. All cases of Wilms tumor were correctly diagnosed by UCNB, but only 33% (3/9) of the other tumors. CONCLUSIONS: In all cases of Wilms tumor a correct diagnosis was made. The overall sensitivity was 76%. UCNB proved to be a safe procedure that was not associated with needle tract recurrence or other serious complications.     

Cancer in infants: a review of 82 cases

Cancer occurring in infants often has clinical and biological properties that are different from those of the same histologic type of cancer occurring in older children. The histologic distribution of cancers in infants and that in older children are also different. The aim of this study was to find these differences between infants and older children, and to compare the percent distribution of infant cancer subtypes with that reported by other countries. The authors collected infant cases diagnosed as having cancer from the database of the Cancer Registry in our Medical Center between 1995 and 2001. Subjects were selected subjects from inpatient logs, and their medical records were reviewed. Eighty-two infants (40 males and 42 females), including 12 neonates, were diagnosed with cancer over this 7-year period. Acute leukemia was diagnosed in 21 infants (25.6%; acute myeloid leukemia in 12, and acute lymphoblastic leukemia in 9), retinoblastoma in 14 (17.1%), neuroblastoma in 12 (14.6%), brain tumor in 9 (11.0%), germ cell tumor in 8 (9.8%), renal cancer in 8 (Wilms tumor 3, mesoblastic nephroma 1, renal sarcoma 1, rhabdoid tumor 3), hepatoblastoma in 5 (6.1%), and soft tissue sarcoma in 5 (rhabdomyosarcoma 1, fibrosarcoma 3, other sarcoma 1). The overall disease-free survival rate was 61.0% (50/82) with a median follow-up duration of 6.8 years for the survivors. The 4 most common types of cancer occurring in infants are the same in the present series and in most larger childhood cancer series reported by other countries; but rank differently. In this study there were more infants with acute leukemia and retinoblastoma, and less with neuroblastoma. The prognosis is poor for infant leukemia and rhabdoid tumor, while it is good for embryonal tumors and germ cell tumors occurring in infancy.     

Surgical tactics in the treatment of malignant renal tumors in childhood

The authors report the treatment results of 89 children with renal tumors (excluding carcinoma) seen from 1988 to 1992, 71 (79.8%) with favorable-histology Wilms' tumor (survival 86%) and 18 (20.2%) with unfavorable histology, including anaplastic nephroblastoma, clear-cell sarcoma, and rhabdoid tumor (survival 61%). Preoperative chemotherapy (ChT) was given to 46 patients (survival 84%); none was given to 43 with either tumors in the 1st year of life, massive hematuria, or tumor growth during ChT (survival 78%). There were 3 tumor ruptures in the latter group compared to 1 in the former group.     

Screening for Wilms tumor in children with Beckwith-Wiedemann syndrome or idiopathic hemihypertrophy

BACKGROUND: Children with Beckwith-Wiedemann syndrome and idiopathic hemihypertrophy (BWS/HH) are at increased risk for developing Wilms tumor and screening with abdominal sonography is frequently recommended. However, there is a paucity of published data supporting this strategy. The purpose of this study was to determine whether sonographic screening at intervals of 4 months or less reduced the proportion of late-stage Wilms Tumor (WT) in children with BWS/HH. PROCEDURE: A case series analysis was employed to compare the proportion of late-stage (stage III or IV) Wilms tumor in patients with BWS/HH who were screened with sonography (n = 15) to the proportion of late-stage Wilms tumor in unscreened patients with BWS/HH (n = 59). Patients were identified from the BWS Registry and from previously published studies. Screened patients had sonograms at intervals of 4 months or less. RESULTS: None of the 12 screened children with Wilms tumor had late-stage disease, whereas 25 of 59 (42%) of unscreened children had late-stage Wilms tumor, a difference that was statistically significant (P < 0.003). Three children had false positive screening studies. They were operated on for suspected Wilms tumor but the lesions proved to be complicated renal cysts (n = 2) or nephroblastomatosis (n = 1). CONCLUSIONS: This study suggests that children with BWS/HH may benefit from screening sonograms at intervals of 4 months or less. However, false positive screening exams may result in unnecessary surgery. Given the rarity of BWS/HH, a larger, prospective international screening study is necessary to determine if the benefits of screening outweigh the risks.     

Complete necrosis induced by preoperative chemotherapy in Wilms tumor as an indicator of low risk: report of the international society of paediatric oncology (SIOP) nephroblastoma trial and study 9

BACKGROUND: The SIOP Nephroblastoma therapeutic protocols include a period of preoperative chemotherapy followed by nephrectomy and a period of postoperative chemotherapy. From the outset, identification of low-risk groups has been an aim of the SIOP Nephroblastoma Trials and Studies. Now that 90% of children with Wilms tumor can be cured, attention is even more focused on the identification of patients who could benefit from less aggressive postoperative therapy, thus minimizing the morbidity and late effects associated with treatment. The prognostic implications of total necrosis in nephroblastoma after chemotherapy have not been investigated hitherto. PROCEDURE: Between November 1, 1987 and June 30, 1993, 599 patients referred to the SIOP-9 Nephroblastoma Trial and Study were preoperatively treated and classified as stages I-IV nonanaplastic Wilms tumor. RESULTS: Of these 599 patients, pathologic examination of the nephrectomy specimen revealed a completely necrotic Wilms tumor (CNWT) with no viable tumor remaining in 59 (10%): these comprised 37 stages I-III and 22 stage IV. Of these patients, 58 (98%) had no evidence of disease at 5 years vs. 90% for the rest of the cohort (P < 0.05). Stages I-III patients represented 63% of CNWT and had a 97% overall survival rate. The only death was related to veno-occlusive disease and occurred in a stage I patient in the month following nephrectomy. Stage IV patients represented 37% of CNWT (vs. only 10% of all other cases of unilateral nonanaplastic Wilms tumor) and had a 100% rate of survival. Children with CNWT were older (mean 59 months vs. 43 months); their tumor at diagnosis was larger and had regressed more significantly at subsequent ultrasound examination. The data also uphold the hypothesis that Wilms tumors of blastemic pattern are most aggressive, but also are extremely responsive to chemotherapy. CONCLUSIONS: Patients with unilateral nonanaplastic WT that showed total necrosis following preoperative chemotherapy had excellent outcome and should benefit from less aggressive postoperative treatment in further trials. Other very responsive tumors, such as Wilms with <10% viable tumor, should also be assessed.     

Current management of Wilms' tumor in children

PurposeWilms’ tumor is the most common renal tumor in children. Outcomes have improved dramatically over the past few decades, but important treatment questions remain. These include the role of molecular biologic markers in stratifying patients for therapy or targeting tumors for treatment. We present a summary of these advances and outline the current treatment of Wilm's tumor.Materials and methodsThe medical literature and results of all cooperative group studies reporting treatment of children with Wilms’ tumor were reviewed.ResultsOverall survival exceeds 90% for most patients with nephroblastoma. However, outcomes for patients with rhabdoid tumors and diffuse anaplasia remain poor. The role of renal sparing surgery in patients with bilateral tumors is clear, but for children with unilateral tumors it continues to be defined.ConclusionsCurrent protocols conducted by pediatric oncology groups are beginning to incorporate biologic features to stratify patients for therapy. Treatment strategies continue to focus on limiting late effects of treatment while maintaining an excellent survival. New therapies are needed to treat the high-risk patients who continue to have high relapse and mortality rates.     

婴幼儿肾脏恶性横纹肌样瘤诊治分析

目的探讨儿童肾脏恶性横纹肌样瘤(malignant rhabdoid tumor of the kidney,MRTK)的临床及病理特点。方法回顾性分析2009年1月至2015年4月本院收治的15例MRTK患儿临床、病理及随访资料。结果 15例患儿中,男性7例,女性8例,年龄3~28个月,平均年龄12.6个月。左侧6例,右侧9例。血尿10例,腹部包块4例,超声发现1例。按NWTS 3进行肿瘤分期:Ⅰ期2例,Ⅱ期5例,Ⅲ期5例,Ⅳ期3例。术前予化疗1例,肾动脉栓塞1例。予保留肾单位的肿瘤剜除术1例,瘤肾切除14例。病理检查结果均提示肾脏恶性横纹肌样瘤。术后化疗14例,放疗4例。11例获随访,9例死亡,2例无瘤存活分别2年、6年,4例失访。结论儿童肾脏恶性横纹肌样瘤好发于婴幼儿,血尿多见,进展迅速,恶性度高,易发生肺脑转移,需要手术+化疗+放疗的综合治疗,预后差。     

Hematuria in children: retrospective study of 128 pediatric patients

OBJECTIVE: To evaluate the diagnostic frequency of the various diseases associated with the development of hematuria in children, in a pediatric nephrology unit pertaining to a university hospital. METHODS: The clinical records of 128 children (70 male, 50 female) who presented intermittent/persistent macroscopic hematuria or persistent microscopic hematuria as the chief clinical complaint/finding, in the period of 1978-1995, were retrospectively analyzed. This evaluation was performed with special attention to the patientacute;s clinical history, physical examination, personal and family morbid history information. Patients whose investigation was not complete were not considered for analysis. The mean age on presentation was 8.2 years (5 months - 16 years) and the mean period of observation was 3.2 years (1 month-15 years). RESULTS: Macroscopic hematuria occurred in 104 patients and persistent microscopic hematuria was present in 24 patients. Urinary metabolic disturbances and urinary lithiasis, alone or in association, were diagnosed in the majority of the patients (65.5%). Hypercalciuria was the urinary metabolic disturbance (90.1%) mostly detected, either alone (73.2%) or in association with hyperuricosuria (16.9%). A positive family history of lithiasis was reported in 32.1% of the patients in which the diagnosis of lithiasis/urinary metabolic disturbance was confirmed. Glomerulopathies were diagnosed in 25% of the patients, with the predominance of post-infectious acute glomerulonephritis (11 patients, 34%). In 6 children, the etiology of hematuria was not elucidated, despite extensive investigation, including renal biopsy.CONCLUSION: The authors present an algorithm for the diagnosis of hematuria in children and suggest that in cases of isolated hematuria, presenting without clinical clues to the possible etiology, laboratory investigation should be started with the evaluation of urinary metabolic disturbances / lithiasis.