APOL1 in an ethnically diverse pediatric population with nephrotic syndrome: implications in focal segmental glomerulosclerosis and other diagnoses.

BACKGROUND: APOL1 high-risk genotypes (HRG) are associated with increased risk of kidney disease in individuals of African ancestry. We analyzed the effects of APOL1 risk variants on an ethnically diverse Brazilian pediatric nephrotic syndrome (NS) cohort. METHODS: Multicenter study including 318 NS patients, categorized as progressors to advanced CKD [estimated glomerular filtration rate (eGFR)] < 30 mL/min/1.73 m2] and slow/non-progressors (eGFR > 30 mL/min/1.73 m2 through the study). We employed Cox regression with progression time as the outcome and APOL1 genotype as the independent variable. We tested this association in the entire cohort and three subgroups; (1) focal segmental glomerulosclerosis (FSGS), (2) steroid-resistant NS (SRNS), and (3) those who underwent kidney biopsy. RESULTS: Nineteen patients (6%) had an HRG. Of these, 47% were self-reported White. Patients with HRG manifested NS at older ages and presented higher frequencies of FSGS and SRNS. HRG patients progressed to advanced CKD more often than low-risk-genotype (LRG) children in the whole NS cohort (p = 0.001) and the three subgroups. In SRNS and biopsied patients, a single risk variant was associated with trends of higher CKD progression risk. CONCLUSIONS: Novel discoveries include a substantial prevalence of HRG among patients self-reported White, worse kidney outcomes in HRG versus LRG children in the FSGS subgroup, and a trend of higher CKD progression risk associated with a single risk variant in the SRNS cohort. These findings suggest APOL1-associated NS extends beyond patients self-reported non-White, the HRG effect is independent of FSGS, and a single risk variant may have a detrimental impact in children with NS.

Promises and pitfalls of whole-exome sequencing exemplified by a nephrotic syndrome family.

High-throughput techniques such as whole-exome sequencing (WES) show promise for the identification of candidate genes that underlie Mendelian diseases such as nephrotic syndrome (NS). These techniques have enabled the identification of a proportion of the approximately 54 genes associated with NS. However, the main pitfall of using WES in clinical and research practice is the identification of multiple variants, which hampers interpretation during downstream analysis. One useful strategy is to evaluate the co-inheritance of rare variants in affected family members. Here, we performed WES of a patient with steroid-resistant NS (SRNS) and intermittent microhematuria. Currently, 15 years after kidney transplantation, this patient presents normal kidney function. The patient was found to be homozygous for a rare MYO1E stop-gain variant, and was heterozygous for rare variants in NS-associated genes, COL4A4, KANK1, LAMB2, ANLN, E2F3, and APOL1. We evaluated the presence or absence of these variants in both parents and 11 siblings, three of whom exhibited a milder phenotype of the kidney disease. Analysis of variant segregation in the family, indicated the MYO1E stop-gain variant as the putative causal variant underlying the kidney disease in the patient and two of her affected sisters. Two secondary variants in COL4A4-identified in some other affected family members-require further functional studies to determine whether they play a role in the development of microhematuria in affected family members. Our data illustrate the difficulties in distinguishing the causal pathogenic variants from incidental findings after WES-based variant analysis, especially in heterogenous genetic conditions, such as NS.

Collaborative Brazilian pediatric renal transplant registry (CoBrazPed-RTx): A report from 2004 to 2018.

The Brazilian collaborative registry for pediatric renal transplantation began in 2004 as a multicenter initiative aimed at analyzing, reporting, and disseminating the results of pediatric renal transplantation in Brazil. Data from all pediatric renal transplants performed from January 2004 to May 2018 at the 13 participating centers were analyzed. A total of 2744 pediatric renal transplants were performed in the thirteen participating centers. The median age at transplantation was 12.2 years, with the majority being male recipients (56%). The main underlying diseases were CAKUT (40.5%) and glomerulopathy (28%). 1981 (72%) of the grafts were from deceased donors (DD). Graft survival at one year (censored by death) was 94% in the live donor group (LD) and 91% in the DD group (log-rank test P < 0.01). The patient's survival at one and 5 years was 97% and 95% for the LD group and 96% and 93% for the DD group (log-rank test P = 0.02). The graft loss rate was 19% (n = 517), more frequently caused by vascular thrombosis (n = 102) and chronic graft nephropathy (n = 90). DD recipients had 1.6 (1.0-2.2) times greater chance of death and 1.5 (1.2-1.8) times greater chance of graft loss compared to LD recipients. The mortality rate was 5.4% (n = 148), mainly due to infection (n = 69) and cardiovascular disease (n = 28). The results of this collaborative pediatric renal transplant record are comparable to other international registries, although we still have a high infection rate as a cause of death.

Pediatric nephrologist-intensivist interaction in acute kidney injury.

INTRODUCTION: Acute Kidney Injury (AKI) in the Intensive Care Unit (ICU) have concepts of diagnosis and management have water balance as their main point of evaluation. In our ICU, from 2004 to 2012, the nephrologist's participation was on demand only; and as of 2013 their participation became continuous in meetings to case discussion. The aim of this study was to establish how an intense nephrologist/intensivist interaction influenced the frequency of dialysis indication, fluid balance and pRIFLE classification during these two observation periods. METHODS: Retrospective study, longitudinal evaluation of all children with AKI undergoing dialysis (2004 to 2016). PARAMETERS STUDIED: frequency of indication, duration and volume of infusion in the 24 hours preceding dialysis; diuresis and water balance every 8 hours. Non-parametric statistics, p ≤ 0.05. RESULTS: 53 patients (47 before and 6 after 2013). There were no significant differences in the number of hospitalizations or cardiac surgeries between the periods. After 2013, there was a significant decrease in the number of indications for dialysis/year (5.85 vs. 1.5; p = 0.000); infusion volume (p = 0.02), increase in the duration of dialysis (p = 0.002) and improvement in the discrimination of the pRIFLE diuresis component in the AKI development. CONCLUSION: Integration between the ICU and pediatric nephrology teams in the routine discussion of cases, critically approaching water balance, was decisive to improve the management of AKI in the ICU.

Dual Molecular Diagnoses of Recessive Disorders in a Child from Consanguineous Parents: Case Report and Literature Review.

The widespread use of whole exome sequencing (WES) resulted in the discovery of multilocus pathogenic variations (MPV), defined as two or more distinct or overlapping Mendelian disorders occurring in a patient, leading to a blended phenotype. In this study, we report on a child with autosomal recessive primary microcephaly-5 (MCPH5) and nephropathic cystinosis. The proband is the first child of consanguineous parents, presenting a complex phenotype including neurodevelopmental delay, microcephaly, growth restriction, significant delay of bone maturation, lissencephaly, and abnormality of neuronal migration, photophobia, and renal tubular acidosis. WES revealed two pathogenic and homozygous variants: a c.4174C>T variant in the ASPM gene and a c.382C>T variant in the CTNS gene, explaining the complex phenotype. The literature review showed that most of the patients harboring two variants in recessive disease genes are born to consanguineous parents. To the best of our knowledge, the patient herein described is the first one harboring pathogenic variants in both the ASPM and CTNS genes. These findings highlight the importance of searching for MPV in patients with complex phenotypes investigated by genome-wide testing methods, especially for those patients born to consanguineous parents.

Pediatric peritoneal dialysis in Brazil: a discussion about sustainability. A document by the Brazilian Society of Nephrology, the Brazilian Society of Pediatrics, the Brazilian Association of Organ Transplantation, and the Brazilian Association of Dialysis and Transplant Centers.

INTRODUçÃO: A diálise peritoneal (DP) é importante para a pediatria. Este estudo mostrou dados de centros brasileiros que utilizam DP pediátrica. MÉTODO: Estudo transversal, observacional, descritivo com questionário eletrônico. Incluiu-se pacientes de 0-18 anos em DP cadastrados nos bancos de dados dos diversos centros. Questionário preenchido anonimamente, sem dados de identificação. Foi adotada metodologia quantitativa. RESULTADOS: 212 pacientes estão em DP no Brasil (agosto, 2021). 80% têm menos de 12 anos de idade. A maioria realiza DP automatizada e 74% são dependentes do Sistema Único de Saúde. Em 25% dos centros faltou material de DP e em 51% os pacientes pediátricos foram convertidos de DP para HD. CONCLUSÃO: A maioria dos pacientes tinha menos de 12 anos e era dependente do SUS. A escassez de insumos aconteceu em 25% dos centros. Esses dados apontam para o problema da sustentabilidade de DP, única alternativa de TRS em crianças muito pequenas.

Pediatric nephrologist-intensivist interaction in acute kidney injury / Interação nefro-intensivista pediátrica na lesão renal aguda

ABSTRACT Introduction: Acute Kidney Injury (AKI) in the Intensive Care Unit (ICU) have concepts of diagnosis and management have water balance as their main point of evaluation. In our ICU, from 2004 to 2012, the nephrologist's participation was on demand only; and as of 2013 their participation became continuous in meetings to case discussion. The aim of this study was to establish how an intense nephrologist/intensivist interaction influenced the frequency of dialysis indication, fluid balance and pRIFLE classification during these two observation periods. Methods: Retrospective study, longitudinal evaluation of all children with AKI undergoing dialysis (2004 to 2016). Parameters studied: frequency of indication, duration and volume of infusion in the 24 hours preceding dialysis; diuresis and water balance every 8 hours. Non-parametric statistics, p ≤ 0.05. Results: 53 patients (47 before and 6 after 2013). There were no significant differences in the number of hospitalizations or cardiac surgeries between the periods. After 2013, there was a significant decrease in the number of indications for dialysis/year (5.85 vs. 1.5; p = 0.000); infusion volume (p = 0.02), increase in the duration of dialysis (p = 0.002) and improvement in the discrimination of the pRIFLE diuresis component in the AKI development. Conclusion: Integration between the ICU and pediatric nephrology teams in the routine discussion of cases, critically approaching water balance, was decisive to improve the management of AKI in the ICU.

RESUMO Introdução: Os conceitos sobre diagnóstico e conduta da Lesão Renal Aguda (LRA) na Unidade de Terapia Intensiva (UTI) tem como ponto primordial a avaliação do balanço hídrico. Em nossa UTI, de 2004 a 2012, a participação do nefrologista era sob demanda. A partir de 2013, a participação passou a ser contínua em reunião de discussão de casos. O objetivo deste estudo foi determinar como a maior interação nefrologista/intensivista influenciou a frequência de indicação de diálise, no balanço hídrico e na classificação pRIFLE durante esses dois períodos de observação. Método: Estudo retrospectivo, avaliação longitudinal de todas as crianças com LRA em diálise (2004 a 2016). Parâmetros estudados: frequência de indicação, tempo de duração e volume de infusão nas 24 horas precedendo a diálise; diurese e balanço hídrico a cada 8 horas. Estatística não paramétrica, p ≤ 0,05. Resultado: 53 pacientes (47 antes e 6 após 2013). Sem diferença significativa no número de internações e nem de cirurgias cardíacas entre os períodos. Após 2013, houve diminuição significativa no número de indicação de diálise/ano (5,85 vs. 1,5; p = 0,000); no volume de infusão (p = 0,02), aumento do tempo de duração da diálise (p = 0,002) e melhora da discriminação do componente diurese do pRIFLE na indicação de LRA. Conclusão: Integração entre equipes de UTI e nefrologia pediátrica na discussão rotineira de casos, abordando criticamente o balanço hídrico, foi determinante para a melhora na conduta da LRA na UTI.

Development of a risk score for earlier diagnosis of chronic kidney disease in children.

OBJECTIVE: To develop a clinical score for the early identification of chronic kidney disease (CKD) in children and adolescents. The early diagnosis of CKD in childhood allows the adoption of measures to slow the progression of the disease, thereby reducing morbidity and mortality. Nevertheless, the diagnosis is often made too late for proper patient management. STUDY DESIGN: We preformed a case-control study of a multicenter Brazilian sample of 752 pediatric patients; the study cases (n = 376) were CKD patients with a median estimated GFR of 37 (IQR = 22 to 57) ml/min/1.73 m2. The control group (n = 376) comprised age-, gender- and center-matched children who were followed for nonrenal diseases. Potential risk factors were investigated through a standard questionnaire that included symptoms, medical history, and a clinical examination. Two multivariable models (A and B) were fitted to assess predictors of the diagnosis of CKD. RESULTS: In model A, 9 variables were associated with CKD diagnosis: antenatal ultrasound with urinary malformation, recurrent urinary tract infection, polyuria, abnormal urine stream, nocturia, growth curve flattening, history of hypertension, foamy urine and edema (c-statistic = 0.938). Model B had the same variables as model A, except for the addition of the history of admission during the neonatal period and the exclusion of antenatal ultrasound variables (c-statistic = 0.927). CONCLUSIONS: The present scores may serve as a warning sign for CKD diagnosis in children among professionals working in the primary care setting where the symptoms associated with a risk of CKD may be overlooked.

Hypercalcemia in children: three cases report with unusual clinical presentations.

Hypercalcemia is a rare condition in childhood; the most common causes are primary hyperparathyroidism, malignancy, prolonged immobilisation, thyrotoxicosis, thiazide diuretic, supplements containing calcium, milk-alkali syndrome, vitamin D intoxication, infections and idiopathic. We present three cases of severe hypercalcemia of unusual causes in children. The first patient had high fever, poor general condition, weight loss and myalgia. Extensive preliminary investigation did not define the etiology, but a review of medical history revealed prolonged contact with pet bird and a positive serology for Chlamydia confirmed the diagnosis of psittacosis. The second patient had generalized lymphadenopathy and hepatosplenomegaly with fever a month ago. Paracoccidioides brasiliensis was identified in myelogram; the patient showed partial improvement with the use of co-trimoxazole, with subsequent emergence of multiple osteolytic lesions. A smear of gastric lavage was positive for Mycobacterium tuberculosis and the patient was treated with rifampicin, isoniazid, ethambutol and pyrazinamide, with improvement of clinical condition. The third patient was treated by hypercalciuria and idiopathic hypomagnesiuria with daily use of cholecalciferol; the patient had a two quilograms of weight loss in the past two months. No cause of hypercalcemia could be detected in laboratory workout. The capsules of cholecalciferol were analyzed and presented an amount of 832,000 IU of vitamin D per capsule. Acute hypercalcemia in childhood may be due to exogenous vitamin D intoxication, as well as infectious causes. The possible causal relationship between psittacosis and occurrence of hypercalcemia alert to the need for detailed investigation of the epidemiological antecedents.

Pediatric peritoneal dialysis in Brazil: a discussion about sustainability. A document by the Brazilian Society of Nephrology, the Brazilian Society of Pediatrics, the Brazilian Association of Organ Transplantation, and the Brazilian Association of Dialysis and Transplant Centers / Diálise peritoneal pediátrica no Brasil: momento de discutir a sustentabilidade. Um documento da Sociedade Brasileira de Nefrologia, Sociedade Brasileira de Pediatria, Associação Brasileira de Transplante de Órgãos e Associação Brasileira de Centros de Diálise e Transplante

Abstract Introdução: A diálise peritoneal (DP) é importante para a pediatria. Este estudo mostrou dados de centros brasileiros que utilizam DP pediátrica. Método: Estudo transversal, observacional, descritivo com questionário eletrônico. Incluiu-se pacientes de 0-18 anos em DP cadastrados nos bancos de dados dos diversos centros. Questionário preenchido anonimamente, sem dados de identificação. Foi adotada metodologia quantitativa. Resultados: 212 pacientes estão em DP no Brasil (agosto, 2021). 80% têm menos de 12 anos de idade. A maioria realiza DP automatizada e 74% são dependentes do Sistema Único de Saúde. Em 25% dos centros faltou material de DP e em 51% os pacientes pediátricos foram convertidos de DP para HD. Conclusão: A maioria dos pacientes tinha menos de 12 anos e era dependente do SUS. A escassez de insumos aconteceu em 25% dos centros. Esses dados apontam para o problema da sustentabilidade de DP, única alternativa de TRS em crianças muito pequenas.

Resumo Introdução: A diálise peritoneal (DP) é importante para a pediatria. Este estudo mostrou dados de centros brasileiros que utilizam DP pediátrica. Método: Estudo transversal, observacional, descritivo com questionário eletrônico. Incluiu-se pacientes de 0-18 anos em DP cadastrados nos bancos de dados dos diversos centros. Questionário preenchido anonimamente, sem dados de identificação. Foi adotada metodologia quantitativa. Resultados: 212 pacientes estão em DP no Brasil (agosto, 2021). 80% têm menos de 12 anos de idade. A maioria realiza DP automatizada e 74% são dependentes do Sistema Único de Saúde. Em 25% dos centros faltou material de DP e em 51% os pacientes pediátricos foram convertidos de DP para HD. Conclusão: A maioria dos pacientes tinha menos de 12 anos e era dependente do SUS. A escassez de insumos aconteceu em 25% dos centros. Esses dados apontam para o problema da sustentabilidade de DP, única alternativa de TRS em crianças muito pequenas.

Hypercalcemia in children: three cases report with unusual clinical presentations / Hipercalcemia em crianças: relato de três casos com apresentações clínicas incomuns

Abstract Hypercalcemia is a rare condition in childhood; the most common causes are primary hyperparathyroidism, malignancy, prolonged immobilisation, thyrotoxicosis, thiazide diuretic, supplements containing calcium, milk-alkali syndrome, vitamin D intoxication, infections and idiopathic. We present three cases of severe hypercalcemia of unusual causes in children. The first patient had high fever, poor general condition, weight loss and myalgia. Extensive preliminary investigation did not define the etiology, but a review of medical history revealed prolonged contact with pet bird and a positive serology for Chlamydia confirmed the diagnosis of psittacosis. The second patient had generalized lymphadenopathy and hepatosplenomegaly with fever a month ago. Paracoccidioides brasiliensis was identified in myelogram; the patient showed partial improvement with the use of co-trimoxazole, with subsequent emergence of multiple osteolytic lesions. A smear of gastric lavage was positive for Mycobacterium tuberculosis and the patient was treated with rifampicin, isoniazid, ethambutol and pyrazinamide, with improvement of clinical condition. The third patient was treated by hypercalciuria and idiopathic hypomagnesiuria with daily use of cholecalciferol; the patient had a two quilograms of weight loss in the past two months. No cause of hypercalcemia could be detected in laboratory workout. The capsules of cholecalciferol were analyzed and presented an amount of 832,000 IU of vitamin D per capsule. Acute hypercalcemia in childhood may be due to exogenous vitamin D intoxication, as well as infectious causes. The possible causal relationship between psittacosis and occurrence of hypercalcemia alert to the need for detailed investigation of the epidemiological antecedents.

Resumo A hipercalcemia é uma condição pouco comum na infância; dentre as causas mais comuns destacam-se hiperparatireoidismo primário, neoplasia, imobilização prolongada, tireotoxicose, diurético tiazídico, suplementos contendo cálcio, síndrome leite-álcali, intoxicação por vitamina D, infecções e causa idiopática. Apresentamos três casos de hipercalcemia grave por causas incomuns em crianças. O primeiro paciente tinha história de febre alta acompanhada de queda do estado geral, emagrecimento e mialgia. Extensa investigação preliminar não definiu a etiologia, porém uma revisão da história clínica revelou contato prolongado com ave de estimação e uma sorologia positiva para clamídia confirmou o diagnóstico de psitacose. O segundo paciente apresentava adenomegalia generalizada e hepatoesplenomegalia acompanhadas de febre por um mês, tendo sido identificado Paracoccidioides brasiliensis no mielograma; o paciente apresentou melhora parcial com uso de sulfametoxazol+trimetoprima, com posterior surgimento de múltiplas lesões osteolíticas. Uma baciloscopia do lavado gástrico foi positiva para Mycobacterium tuberculosis, tratado com rifampicina, isoniazida, pirazinamida e etambutol, com boa evolução. O terceiro paciente já era acompanhado por hipercalciúria e hipomagnesiúria idiopáticas e fazia uso diário de colecalciferol; perdeu dois quilogramas nos últimos dois meses. Nenhuma causa de hipercalcemia pôde ser detectada nos exames laboratoriais. As cápsulas de colecalciferol foram analisadas e encontrou-se uma quantidade de 832.000 UI de vitamina D. A hipercalcemia aguda na infância pode ser decorrente de intoxicação exógena por vitamina D, bem como de causas infecciosas. A possível relação causal entre psitacose e ocorrência da hipercalcemia alerta para a necessidade de investigação detalhada dos antecedentes epidemiológicos.

Frasier syndrome: four new cases with unusual presentations.

Frasier syndrome (FS) is characterized by gonadal dysgenesis and nephropathy. It is caused by specific mutations in the Wilms' tumor suppressor gene (WT1) located in 11p23. Patients with the 46,XY karyotype present normal female genitalia with streak gonads, and have higher risk of gonadal tumor, mainly, gonadoblastoma. Therefore, elective bilateral gonadectomy is indicated. Nephropathy in FS consists in nephrotic syndrome (NS) with proteinuria that begins early in childhood and progressively increases with age, mainly due to nonspecific focal and segmental glomerular sclerosis (FSGS). Patients are generally unresponsive to steroid and immunosuppressive therapies, and will develop end-stage renal failure (ESRF) during the second or third decade of life. We report here four cases of FS diagnosis after identification of WT1 mutations. Case 1 was part of a large cohort of patients diagnosed with steroid-resistant nephrotic syndrome, in whom the screening for mutations within WT1 8-9 hotspot fragment identified the IVS9+5G>A mutation. Beside FS, this patient showed unusual characteristics, such as urinary malformation (horseshoe kidney), and bilateral dysgerminoma. Cases 2 and 3, also bearing the IVS9+5G>A mutation, and case 4, with IVS9+1G>A mutation, were studied due to FSGS and/or delayed puberty; additionally, patients 2 and 4 developed bilateral gonadal tumors. Since the great majority of FS patients have normal female external genitalia, sex reversal is not suspected before they present delayed puberty and/or primary amenorrhea. Therefore, molecular screening of WT1 gene is very important to confirm the FS diagnosis.

[Short stature in chronic kidney disease: physiopathology and treatment with growth hormone]. / Baixa estatura na doença renal crônica: fisiopatologia e tratamento com hormônio de crescimento.

Growth failure is frequent and a clinically important issue in children with chronic kidney disease (CKD). Many factors contribute to impaired growth in these children, including abnormalities in the growth hormone (GH)--insulin-like growth factor 1 (IGF-1) axis, malnutrition, acidosis, renal bone disease and glucocorticoid associated treatment. The management of growth failure in children with CKD is complicated by the presence of other-disease related complications requiring medical intervention. Despite evidence of GH efficacy and safety in this population, this therapy is still underutilized. This review shows the impact, the causes and the treatment of growth failure in children with CKD.

Mutations in the vitamin D receptor gene in four patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets.

Mutations in the vitamin D receptor (VDR) are associated to the hereditary 1,25-dihydroxivitamin D-resistant rickets. The objectives of this work are: search for mutations in the VDR and analyze their functional consequences in four Brazilian children presented with rickets and alopecia. The coding region of the VDR was amplified by PCR e direct sequenced. We identified three mutations: two patients had the same mutation in exon 7 at aminoacid position 259 (p.Q259E); one patient had a mutation in exon 8 at codon 319 (p.G319V) and another one had a mutation in exon 3 leading to a truncated protein at position 73 (p.R73X). Functional studies of the mutant receptors of fibroblast primary culture, from patients' skin biopsy treated with increasing doses of 1,25(OH)2 vitamin D showed that VDR mutants were unable to be properly activated and presented a reduction in 24-hydroxylase expression level.

Apparent mineralocorticoid excess syndrome in a Brazilian boy caused by the homozygous missense mutation p.R186C in the HSD11B2 gene.

The apparent mineralocorticoid excess syndrome (AME) is a rare autosomal recessive disorder due to the deficiency of 11beta-hydroxysteroid dehydrogenase type 2 enzyme (11beta-HSD2). The 11beta-HSD2 enzyme, encoded by HSD11B2 gene, metabolizes active cortisol in cortisone. Mutations on HSD11B2 gene affect the enzyme activity by leading to an excess of cortisol, which causes its inappropriate access to mineralocorticoid receptor. Therefore, cortisol will bind mineralocorticoid receptor. The human HSD11B2 gene maps to chromosome 16q22 and consists of five exons encoding a protein of 405 amino acids. We present here clinical and molecular studies on a Brazilian boy who was born pre-term after an oligodramnious pregnancy. He was diagnosed as having AME at the age of 26 months. His parents are second cousins. Molecular characterization of the HSD11B2 gene revealed the homozygous mutation p.R186C. The patient described here is the second case of HDS11B2 gene mutation reported in Brazilian patients with AME.

Frasier syndrome: four new cases with unusual presentations / Síndrome de Frasier: quatro novos casos com apresentação atípica

Frasier syndrome (FS) is characterized by gonadal dysgenesis and nephropathy. It is caused by specific mutations in the Wilms' tumor suppressor gene (WT1) located in 11p23. Patients with the 46,XY karyotype present normal female genitalia with streak gonads, and have higher risk of gonadal tumor, mainly, gonadoblastoma. Therefore, elective bilateral gonadectomy is indicated. Nephropathy in FS consists in nephrotic syndrome (NS) with proteinuria that begins early in childhood and progressively increases with age, mainly due to nonspecific focal and segmental glomerular sclerosis (FSGS). Patients are generally unresponsive to steroid and immunosuppressive therapies, and will develop end-stage renal failure (ESRF) during the second or third decade of life. We report here four cases of FS diagnosis after identification of WT1 mutations. Case 1 was part of a large cohort of patients diagnosed with steroid-resistant nephrotic syndrome, in whom the screening for mutations within WT1 8-9 hotspot fragment identified the IVS9+5G>A mutation. Beside FS, this patient showed unusual characteristics, such as urinary malformation (horseshoe kidney), and bilateral dysgerminoma. Cases 2 and 3, also bearing the IVS9+5G>A mutation, and case 4, with IVS9+1G>A mutation, were studied due to FSGS and/or delayed puberty; additionally, patients 2 and 4 developed bilateral gonadal tumors. Since the great majority of FS patients have normal female external genitalia, sex reversal is not suspected before they present delayed puberty and/or primary amenorrhea. Therefore, molecular screening of WT1 gene is very important to confirm the FS diagnosis. Arq Bras Endocrinol Metab. 2012;56(8):525-32.

A síndrome de Frasier (SF), caracterizada por disgenesia gonadal e nefropatia, é causada por mutações específicas no gene supressor do tumor de Wilms (WT1) localizado em 11p23. Pacientes com cariótipo 46,XY apresentam genitália feminina normal com gônadas disgenéticas e alto risco de tumor gonadal, principalmente o gonadoblastoma. Por isso, a gonadectomia bilateral eletiva está indicada. A nefropatia na SF consiste de síndrome nefrótica com proteinúria que se inicia na infância e aumenta progressivamente com a idade, principalmente devido à glomeruloesclerose focal e segmentar (GESF). Esses pacientes não respondem ao tratamento com esteroides e imunossupressores e desenvolverão insuficiência renal crônica durante a segunda ou terceira década de vida. Neste trabalho, são relatados quatro casos de SF cujo diagnóstico foi definido após o rastreamento molecular do gene WT1. O caso 1 faz parte de um grande grupo de pacientes que tiveram diagnóstico de síndrome nefrótica corticorresistente e no qual o rastreamento de mutações no fragmento 8-9 do gene WT1 identificou a mutação IVS9+5G>A. Além da SF, essa paciente apresentou características incomuns, tais como malformação urinária (rins em ferradura) e disgerminoma bilateral. Os casos 2 e 3 também apresentaram a mutação IVS9+5G>A, e, no caso 4, foi identificada a mutação IVS9+1G>A, sendo que esses três casos foram encaminhados para estudo molecular em decorrência de GESF e/ou atraso no desenvolvimento puberal. Além disso, as pacientes 2 e 4 desenvolveram tumor gonadal bilateral. Visto que a maioria dos pacientes com SF apresenta genitália externa feminina, não há suspeita de sexo reverso até apresentarem atraso puberal e/ou amenorreia primária. Portanto, o rastreamento molecular do gene WT1 é de fundamental importância para se confirmar o diagnóstico de SF. Arq Bras Endocrinol Metab. 2012;56(8):525-32.