RESUMO
Historically, specific mutations in WT1 gene have been associated with distinct syndromes based on phenotypic characteristics, including Denys-Drash syndrome (DDS), Frasier syndrome (FS), Meacham syndrome, and WAGR syndrome. DDS is classically defined by the triad of steroid-resistant nephrotic syndrome (SRNS) onset in the first year of life, disorders of sex development (DSD), and a predisposition to Wilms tumor (WT). Currently, a paradigm shift acknowledges a diverse spectrum of presentations beyond traditional syndromic definitions. Consequently, the concept of WT1-related disorders becomes more precise. A genotype-phenotype correlation has been established, emphasizing that the location and type of WT1 mutations significantly influence the clinical presentation, the condition severity, and the chronology of patient manifestations. Individuals presenting with persistent proteinuria, with or without nephrotic syndrome, and varying degrees of kidney dysfunction accompanied by genital malformations should prompt suspicion of WT1 mutations. Recent genetic advances enable a more accurate estimation of malignancy risk in these patients, facilitating a conservative nephron-sparing surgery (NSS) approach in select cases, with a focus on preserving residual kidney function and delaying nephrectomies. Other key management strategies include kidney transplantation and addressing DSD and gonadoblastoma. In summary, recent genetic insights underscore the imperative to implement individualized, integrated, and multidisciplinary management strategies for WT1-related disorders. This approach is pivotal in optimizing patient outcomes and addressing the complexities associated with these diverse clinical manifestations.
Assuntos
Síndrome de Denys-Drash , Mutação , Proteínas WT1 , Humanos , Síndrome de Denys-Drash/genética , Síndrome de Denys-Drash/diagnóstico , Síndrome de Denys-Drash/terapia , Proteínas WT1/genética , Fenótipo , Síndrome Nefrótica/genética , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/terapia , Tumor de Wilms/genética , Tumor de Wilms/terapia , Tumor de Wilms/diagnóstico , Síndrome de Frasier/genética , Síndrome de Frasier/terapia , Síndrome de Frasier/diagnósticoRESUMO
BACKGROUND : Nephropathy in Denys-Drash syndrome (DDS) develops within a few months of birth, often progressing to kidney failure. Wilms tumors also develop at an early age with a high rate of incidence. When a patient does not have Wilms tumor but develops kidney failure, prophylactic bilateral nephrectomy, and kidney transplantation (KTX) is an optimal approach owing to the high risk of Wilms tumor development. In the case presented here, prophylactic bilateral nephrectomy and KTX were performed in a patient who had not developed Wilms tumor or kidney failure. However, the treatment option is controversial as it involves the removal of a tumor-free kidney and performing KTX in the absence of kidney failure. CASE DIAGNOSIS/TREATMENT: We present the case of a 7-year-old boy, born at 38 weeks gestation. Examinations at the age of 1 year revealed severe proteinuria and abnormal internal and external genitalia. Genetic testing identified a missense mutation in exon 9 of the WT1 gene, leading to the diagnosis of DDS. At the age of 6 years, he had not yet developed Wilms tumor and had grown to a size that allowed him to safely undergo a KTX. His kidney function was slowly deteriorating (chronic kidney disease (CKD) stage 3), but he had not yet developed kidney failure. Two treatment options were considered for this patient: observation until the development of kidney failure or prophylactic bilateral nephrectomy with KTX to avoid Wilms tumor development. After a detailed explanation of options to the patient and family, they decided to proceed with prophylactic bilateral nephrectomy and KTX. At the latest follow-up 4 months after KTX, the patient's kidney functioned well without proteinuria. CONCLUSION: We performed prophylactic bilateral nephrectomy with KTX on a DDS patient who had not developed kidney failure or Wilms tumor by the age of 7 years. Although the risk of development of Wilms tumor in such a patient is unclear, this treatment may be an optimal approach for patients who are physically able to undergo KTX, considering the potentially lethal nature of Wilms tumor in CKD patients.
Assuntos
Síndrome de Denys-Drash , Neoplasias Renais , Transplante de Rim , Insuficiência Renal Crônica , Insuficiência Renal , Tumor de Wilms , Masculino , Humanos , Criança , Síndrome de Denys-Drash/complicações , Síndrome de Denys-Drash/genética , Síndrome de Denys-Drash/cirurgia , Transplante de Rim/efeitos adversos , Tumor de Wilms/complicações , Tumor de Wilms/cirurgia , Tumor de Wilms/genética , Genes do Tumor de Wilms , Insuficiência Renal/genética , Nefrectomia/efeitos adversos , Neoplasias Renais/complicações , Neoplasias Renais/cirurgia , Neoplasias Renais/genética , Insuficiência Renal Crônica/genética , Proteinúria/genética , Proteínas WT1/genéticaRESUMO
An induced pluripotent stem cell (hiPSC) line (MPIi008-A) was generated from fibroblasts of a 1-year-old male patient with Denys-Drash syndrome using lentiviral delivery of reprogramming factors OCT4, SOX2, KLF4 and c-MYC. The MPIi008-A iPSC line exhibited typical iPSC morphology and normal karyotype, expressed pluripotent stem cell markers, and showed developmental potential to differentiate into derivatives of all three germ layers in vivo. The hiPSC line harbours a heterozygous missense mutation (R394L) in exon 9 of the WT1 gene.
Assuntos
Síndrome de Denys-Drash , Células-Tronco Pluripotentes Induzidas , Células-Tronco Pluripotentes , Diferenciação Celular , Síndrome de Denys-Drash/metabolismo , Fibroblastos/metabolismo , Heterozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Lactente , Masculino , MutaçãoRESUMO
OBJECTIVES: Wilm's Tumor (WT) is the most common pediatric kidney cancer. Whereas most WTs are isolated, approximately 5% are associated with syndromes such as Denys-Drash (DDS), characterized by early onset nephropathy, disorders of sex development and predisposition to WT. CASE PRESENTATION: A 46,XY patient presenting with bilateral WT and genital ambiguity without nephropathy was heterozygous for the novel c.851_854dup variant in WT1 gene sequence. This variant affects the protein generating the frameshift p.(Ser285Argfs*14) that disrupts a nuclear localization signal (NLS) region. CONCLUSIONS: This molecular finding is compatible with the severe scenario regarding the Wilm's tumor presented by the patient even though nephropathy was absent.
Assuntos
Síndrome de Denys-Drash , Neoplasias Renais , Tumor de Wilms , Criança , Síndrome de Denys-Drash/genética , Síndrome de Denys-Drash/patologia , Genes do Tumor de Wilms , Heterozigoto , Humanos , Neoplasias Renais/genética , Proteínas WT1/genética , Tumor de Wilms/genéticaRESUMO
BACKGROUND: Intronic WT1 mutations are usually causative of Frasier syndrome with focal segmental glomerulosclerosis as the characteristic nephropathy. Membranoproliferative glomerulonephritis is not commonly associated with disorders of sex development but has been recently identified as a WT1-associated nephropathy, but usually in cases of exonic mutations in either isolated Wilms tumor or Denys-Drash syndrome. METHODS: The clinical and genetic data from 3 individuals are reported. RESULTS: This report describes the kidney manifestations in 3 individuals from 2 unrelated families with Frasier syndrome intronic WT1 mutations, noting that 2 of the 3 individuals have histologically confirmed membranoproliferative glomerulonephritis. CONCLUSIONS: These case reports support expansion of the clinical spectrum of the kidney phenotypes associated with Frasier syndrome providing evidence of an association between WT1 mutation and an immune complex-related membranoproliferative glomerulonephritis. A higher resolution version of the Graphical abstract is available as Supplementary information.
Assuntos
Síndrome de Denys-Drash , Glomerulonefrite Membranoproliferativa , Disgenesia Gonadal , Neoplasias Renais , Tumor de Wilms , Síndrome de Denys-Drash/genética , Síndrome de Denys-Drash/patologia , Síndrome de Frasier/genética , Genes do Tumor de Wilms , Glomerulonefrite Membranoproliferativa/genética , Disgenesia Gonadal/genética , Humanos , Neoplasias Renais/genética , Mutação , Proteínas WT1/genética , Tumor de Wilms/genéticaRESUMO
RATIONALE: Pediatric patients with WTl-associated syndromes (including Wilms' tumor-aniridia syndrome and Denys-Drash syndrome), Perlman syndrome, mosaic aneuploidy, and Fanconi anemia with a biallelic breast cancer type 2 susceptibility protein mutation have the highest risk of developing Wilms' tumor. PATIENT CONCERNS AND DIAGNOSIS: We describe a patient with bilateral metachronous Wilms' tumor, ambiguous genitalia characterized by 46, XY disorder of sexual development (DSD) with scrotal hypospadias and bilateral abdominal cryptorchidism, but without nephropathy. At the age of 7 months, the child underwent left nephrectomy with left orchiopexy. At follow-up after 8 months, a second tumor with a diameter of 10 mm was detected in abdominal CT scans at the lower pole of the right kidney. INTERVENTION: Intra-operative macroscopic inspection of the right kidney revealed a tight attachment of the right proximal ureter to the tumor. Thus, retroperitoneoscopic resection of the lower pole of the right kidney had to be changed to an open surgical procedure with partial resection of the proximal ureter and high uretero-ureterostomy. We subsequently performed orchiopexy and two-stage correction of hypospadias using a free skin graft. OUTCOMES: At the last follow-up at the age of 8âyears, no pathology requiring treatment was noted. A pair-end-reading (2â×â125) DNA analysis with an average coverage of at least 70 to 100â×ârevealed a previously unknown heterozygous mutation in exon 7 of the Wilms' tumor suppressor gene 1 (WT1) gene (chr11:32417947G>A), leading to the appearance of a site of premature translation termination in codon 369 (p.Arg369Ter, NM_024426.4). This mutation had not been registered previously in the control samples "1000 genomes," Exome Sequencing Project 6500, and the Exome Aggregation Consortium. Thus, to the best of our knowledge this represents a newly identified mutation causing incomplete Denys-Drash syndrome.
Assuntos
Síndrome de Denys-Drash/genética , Síndrome de Denys-Drash/patologia , Genes do Tumor de Wilms/fisiologia , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/patologia , Criança , Humanos , Lactente , Recém-Nascido , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , MasculinoRESUMO
OBJECTIVE: Denys-Drash syndrome (DDS) is defined by the triad of Wilms tumor, nephrotic syndrome, and/or ambiguous genitalia. Genetic testing may help identify new gene mutation sites and play an important role in clinical decision-making. METHODS: We present a patient with an XY karyotype and female appearance, nephropathy, and Wilms tumor in the right kidney. Genomic DNA was extracted from peripheral blood cells according to standard protocols. "Next-generation" sequencing (NGS) was performed to identify novel variants. The variant was analyzed with Mutation Taster, and its function was explored by a cell growth inhibition assay. RESULTS: We found the first case of Denys-Drash syndrome with the uncommon missense mutation (c.1420C>T, p.His474 Tyr) in the WT1 gene. In silico analysis, the variant was predicted "disease-causing" by Mutation Taster. The mutated variant showed a weaker effect in inhibiting tumor cells than wild-type WT1. CONCLUSIONS: The uncommon missense mutation (c.1420C>T, p.His474 Tyr) in the WT1 gene may be a crucial marker in DDS.
Assuntos
Povo Asiático/genética , Síndrome de Denys-Drash/genética , Proteínas WT1/genética , Tumor de Wilms/genética , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular Tumoral , China , Simulação por Computador , Feminino , Seguimentos , Humanos , Lactente , Laparoscopia , Mutação , Linhagem , Tomografia Computadorizada por Raios X , Proteínas WT1/química , Tumor de Wilms/diagnóstico , Tumor de Wilms/diagnóstico por imagemRESUMO
Introduction: Denys-Drash Syndrome (DDS) consists of a triad of pseudohermaphroditism, Wilms'tumor and nephropathy. This condition may manifest as a complete triad or in an incomplete form; with either one or a combination of the above features. The characteristic glomerular abnormality in DDS is diffuse mesangial sclerosis (DMS).Case report: We report two cases of DDS with focal membranoproliferative glomerulonephritis (MPGN). Both of our cases were males with ambiguous genitalia. They had a similar heterozygous germline mutation in exon 9 of WT1, c.1180C>T, p.R394W; a known mutation hotspot for DDS. Case 1 had nephropathy at the age of 4 years and Case 2 at 2.5 years with different rates of progression to end-stage renal failure. Conclusion: Our findings, in combination with other reports, illustrate the clinicopathological heterogeneity of DDS. There are no universal recommendations for optimal management of patients with DDS due to the inability to accurately predict affected individuals' progress.
Assuntos
Síndrome de Denys-Drash , Glomerulonefrite Membranoproliferativa , Nefropatias , Síndrome Nefrótica , Tumor de Wilms , Pré-Escolar , Síndrome de Denys-Drash/genética , Genes do Tumor de Wilms , Glomerulonefrite Membranoproliferativa/genética , Humanos , Masculino , Mutação , Síndrome Nefrótica/genética , Proteínas WT1/genética , Tumor de Wilms/genéticaRESUMO
We describe a 46,XX girl with Denys-Drash syndrome, showing both kidney disease and genital abnormalities, in whom a misdiagnosis of hyperandrogenism was made. A 15 year-old girl was affected by neonatal nephrotic syndrome, progressing to end stage kidney failure. Hair loss and voice deepening were noted during puberty. Pelvic ultrasound and magnetic resonance imaging showed utero-tubaric agenesis, vaginal atresia and urogenital sinus, with inguinal gonads. Gonadotrophin and estradiol levels were normal, but testosterone was increased up to 285 ng/dL at Tanner stage 3. She underwent prophylactic gonadectomy. Histopathology reported fibrotic ovarian cortex containing numerous follicles in different maturation stages and rudimental remnants of Fallopian tubes. No features of gonadoblastoma were detected. Unexpectedly, testosterone levels were elevated four months after gonadectomy (157 ng/dL). Recent medical history revealed chronic daily comsumption of high dose biotin, as a therapeutic support for hair loss. Laboratory immunoassay instruments used streptavidin-biotin interaction to detect hormones and, in competitive immunoassays, high concentrations of biotin can result in false high results. Total testosterone, measured using liquid chromatography tandem mass spectrometry, was within reference intervals. Similar testosterone levels were detected on repeat immunoassay two weeks after biotin uptake interruption. Discordance between clinical presentation and biochemical results in patients taking biotin, should raise the suspicion of erroneous results. Improved communication among patients, health care providers, and laboratory professionals is required concerning the likelihood of biotin interference with immunoassays.
Assuntos
Biotina/efeitos adversos , Síndrome de Denys-Drash/genética , Suplementos Nutricionais/efeitos adversos , Adolescente , Castração , Síndrome de Denys-Drash/complicações , Síndrome de Denys-Drash/diagnóstico , Síndrome de Denys-Drash/terapia , Erros de Diagnóstico , Feminino , Humanos , Hiperandrogenismo/sangue , Hiperandrogenismo/diagnóstico , Hiperandrogenismo/cirurgia , Imunoensaio , Falência Renal Crônica/etiologia , Valor Preditivo dos Testes , Testosterona/sangueRESUMO
A term infant with prenatally noted ambiguous genitalia and nonpalpable gonads presented with life-threatening hyponatremia, hypertension, acidosis, and anuric renal failure requiring peritoneal dialysis at age 3 months.Sequencing confirmed 46, XY Denys-Drash syndrome (DDS) due to heterozygous Wilms tumor-1 exon 8 mutation encoding p.His445Arg. Renal US identified bilateral multifocal renal masses at age 8 months. Bilateral retroperitoneal nephrectomies found bilateral nephroblastomatosis without Wilms' tumor avoiding chemotherapy, followed by bilateral laparoscopic orchiopexies. We suggest monthly screening of 46, XY DSD cases for DDS by evaluating for proteinuria and electrolyte disarray starting at diagnosis of DSD to prevent acute life-threatening renal failure presentation.
Assuntos
Síndrome de Denys-Drash/diagnóstico , Transtornos do Desenvolvimento Sexual/diagnóstico , Congressos como Assunto , Síndrome de Denys-Drash/sangue , Síndrome de Denys-Drash/complicações , Síndrome de Denys-Drash/genética , Transtornos do Desenvolvimento Sexual/sangue , Transtornos do Desenvolvimento Sexual/complicações , Transtornos do Desenvolvimento Sexual/genética , Diagnóstico Precoce , Eletrólitos/sangue , Feminino , Humanos , Lactente , Oncologia , Pediatria , Proteinúria/complicações , Proteinúria/diagnóstico , Sociedades Médicas , Urologia , RedaçãoRESUMO
Denys-Drash syndrome is characterized by progressive nephropathy, gonadal dysgenesis, and Wilms tumor caused by a WT1 gene mutation. Infants with Denys-Drash syndrome frequently experience severe hypertension, but detailed clinical manifestations have yet to be clarified. Cases of infantile-onset Denys-Drash syndrome with severe hypertension at our hospital were retrospectively analyzed and the pathogenesis of hypertension was investigated. Six infants who received the diagnosis of Denys-Drash syndrome at the median age of 10 days (range: 2-182 days) were enrolled. Five infants had the complication of severe hypertension within a few days of diagnosis. All the patients showed rapid progression to end-stage renal disease and urgently required dialysis due to anuria/oliguria and hypervolemia with a median duration of 7.5 days (range: 0-17 days) on the day after diagnosis. Even under dialysis, all the patients continued to need antihypertensive treatment. Five patients underwent a preventive nephrectomy for Wilms tumor, and one patient underwent a nephrectomy due to progression to Wilms tumor. Two patients developed hypotension after a nephrectomy. The main causes of hypertension were hypervolemia in the predialysis stage, renin-associated hypertension in the dialysis stage, and multiple factors, including increased plasma catecholamine-associated hypertension in the postnephrectomy dialysis stage. At last the follow-up after bilateral nephrectomy, four of the five patients required antihypertensive treatment. Not all the patients showed target organ complications caused by hypertension. Severe hypertension is a common complication of infantile-onset Denys-Drash syndrome. The possibility of hypotension after nephrectomy should be considered in patients with Denys-Drash syndrome.
Assuntos
Síndrome de Denys-Drash/complicações , Hipertensão/complicações , Idade de Início , Síndrome de Denys-Drash/cirurgia , Humanos , Hipertensão/cirurgia , Hipotensão/complicações , Lactente , Recém-Nascido , Nefrectomia , Especificidade de ÓrgãosRESUMO
BACKGROUND: Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) cause substantial morbidity and mortality. In Japan, there is a lack of knowledge regarding the characteristics of CNS and INS. This study aimed to clarify the characteristics of CNS and INS in Japan. METHODS: This cross-sectional nationwide survey obtained data from 44 institutions in Japan managing 92 patients with CNS or INS, by means of two survey questionnaires sent by postal mail. Patients aged < 16 years by 1 April 2015, with a diagnosis of CNS or INS, were included in this study. The primary outcome was end-stage kidney disease. RESULTS: A total of 83 patients with CNS or INS were analyzed. The most frequent disease type was non-Finnish (60.2%); 33 patients (39.8%) had Finnish type. Among those with non-Finnish-type disease, 26 had no syndrome and 24 had a syndrome, of which the most frequent was Denys-Drash syndrome (70.8%). Patients with non-Finnish-type disease with syndrome showed the earliest progression to end-stage kidney disease compared with the other two groups, whereas patients with non-Finnish-type disease without syndrome progressed more slowly compared with the other two groups. In the Finnish-type group, the disease was diagnosed the earliest; a large placenta was reported more frequently; genetic testing was more frequently performed (93.8%); mental retardation was the most frequent extra-renal symptom (21.2%); and thrombosis and infection were more frequent compared with the other groups. Patients with non-Finnish-type disease with syndrome had a higher frequency of positive extra-renal symptoms (79.2%), the most common being urogenital symptoms (54.2%). Treatment with steroids and immunosuppressants was more frequent among patients with non-Finnish-type disease without syndrome. Two patients with non-Finnish-type disease without syndrome achieved complete remission. In all groups, unilateral nephrectomy was performed more often than bilateral nephrectomy and peritoneal dialysis was the most common renal replacement therapy. CONCLUSIONS: The present epidemiological survey sheds light on the characteristics of children with CNS and INS in Japan. A high proportion of patients underwent genetic examination, and patient management was in accord with current treatment recommendations and practices. TRIAL REGISTRATION: Not applicable.
Assuntos
Deficiência Intelectual/fisiopatologia , Falência Renal Crônica/fisiopatologia , Síndrome Nefrótica/fisiopatologia , Adolescente , Criança , Pré-Escolar , Síndrome de Denys-Drash/patologia , Síndrome de Denys-Drash/fisiopatologia , Progressão da Doença , Feminino , Testes Genéticos , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Lactente , Recém-Nascido , Japão , Estimativa de Kaplan-Meier , Falência Renal Crônica/terapia , Masculino , Síndromes Miastênicas Congênitas/patologia , Síndromes Miastênicas Congênitas/fisiopatologia , Nefrectomia , Síndrome Nefrótica/congênito , Síndrome Nefrótica/patologia , Síndrome Nefrótica/terapia , Tamanho do Órgão , Placenta/patologia , Gravidez , Distúrbios Pupilares/patologia , Distúrbios Pupilares/fisiopatologia , Terapia de Substituição Renal , Inquéritos e Questionários , SíndromeRESUMO
BACKGROUND: Neonatal-onset Denys-Drash syndrome (NODDS) is a distinctive clinical entity and has a poor renal and life outcome. Early diagnosis of NODDS is important for managing disorders of sexual development and determining assigned gender. Although patients with NODDS and congenital nephrotic syndrome of the Finnish type (CNF) present with nephrotic syndrome in neonatal life or infancy, the clinical course of NODDS and factors distinguishing these diseases at onset is unknown. METHODS: We performed a retrospective cohort study of patients with NODDS and CNF between 1997 and 2017. Patients with nephrotic syndrome and WT1 or NPHS1 mutations with neonatal onset (within 30 days) were eligible. RESULTS: We studied eight patients with NODDS and 15 with CNF. The median serum creatinine level at onset in the NODDS group was significantly higher (1.85 mg/dL) than that in the CNF group (0.15 mg/dL; P = 0.002). The median placental/fetal weight ratio in the NODDS and CNF group was 41.8% and 21.0%, respectively (P = 0.001). Kaplan-Meier analysis showed that the median number of days for progression to ESRD from onset in the NODDS and CNF groups was 6 and 910 days, respectively (P < 0.001). All patients in the NODDS group were alive at follow-up. Only one patient in the CNF group died of cardiac complications during follow-up. CONCLUSION: CNS, renal dysfunction at onset, and a relatively large placenta are prominent signs of NODDS. Prognosis for patients with NODDS is satisfactory if appropriate and active management is performed.
Assuntos
Síndrome de Denys-Drash/complicações , Falência Renal Crônica/etiologia , Síndrome Nefrótica/complicações , Adolescente , Idade de Início , Criança , Pré-Escolar , Síndrome de Denys-Drash/diagnóstico , Síndrome de Denys-Drash/genética , Síndrome de Denys-Drash/terapia , Progressão da Doença , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/terapia , Proteínas de Membrana/genética , Mutação , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/genética , Síndrome Nefrótica/terapia , Fenótipo , Diálise Renal , Estudos Retrospectivos , Fatores de Risco , Tóquio , Proteínas WT1/genéticaAssuntos
Síndrome de Denys-Drash/cirurgia , Terapia de Imunossupressão/efeitos adversos , Transplante de Rim/efeitos adversos , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Mycobacterium marinum/isolamento & purificação , Adulto , Biópsia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Hospedeiro Imunocomprometido , Terapia de Imunossupressão/métodos , Masculino , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium marinum/imunologia , Pele/microbiologia , Pele/patologia , Extremidade SuperiorRESUMO
Denys Drash Syndrome (DDS) is a rare combination of genital and urinary anomalies that are mostly associated with malignancy. We report 2 patients who presented with genital ambiguity and were diagnosed as 46-XY DDS. During the discussion of the management plan, parents preferred to keep the gonads to preserve its endocrinal function for future sexual development. However, both patients developed primary hypogonadism at puberty and required testosterone supplementation. Persevering gonads in such patients had no endocrinal benefits but put the patients at risk of malignant transformation.
Assuntos
Síndrome de Denys-Drash/genética , Síndrome de Denys-Drash/cirurgia , Tratamentos com Preservação do Órgão , Testículo/fisiologia , Testículo/cirurgia , Adolescente , Cromossomos Humanos X , Cromossomos Humanos Y , Criptorquidismo/genética , Criptorquidismo/cirurgia , Disfunção Erétil , Seguimentos , Humanos , Hipogonadismo , Transplante de Rim , Masculino , Mutação , Síndrome Nefrótica/complicações , Síndrome Nefrótica/cirurgia , Maturidade Sexual , Testículo/patologia , Testosterona/uso terapêutico , Anormalidades Urogenitais/cirurgia , Tumor de Wilms/complicações , Tumor de Wilms/cirurgia , Adulto JovemRESUMO
Objective: To explore the clinical and pathological features and mutational types and their relations with WT1 mutation-associated nephropathy (WT1MAN). Methods: The clinical and pathological data and the results of WT1 mutation analysis of the cases from Nanfang Hospital of Southern Medical University, Sun Yat-sen Memorial Hospital and The First Affiliated Hospital of Sun Yat-sen University whom we recruited recently and reported during the last ten years were analyzed. Results: Totally, 20 cases (6 males and 14 females), included 5 newly diagnosed cases, were recruited. (1) Ten children were diagnosed with Denys-Drash syndrome (DDS): The median onset age of proteinuria was 1 year and 7 months. Diffuse mesangial sclerosis (DMS) were revealed in 3 cases, minimal lesions (MCD) in 4 cases, and focal segmental glomerulosclerosis (FSGS) in 1 case; renal pathology was not available in the other 2 cases. Glomerular basement membrane (GBM) thickening was observed in 2 cases. Calcineurin inhibitors (CNIs) were administered in 5 cases, complete remission of proteinuria was observed in 3 cases, partial remission in the other 2 cases. Genetic analysis revealed that six cases had WT1 missense mutation, 3 had nonsense mutation, and 1 had frameshift mutation. (2) Two cases were diagnosed with Frasier syndrome (FS): proteinuria was observed at 1 year and 1 month of age and 1 year and 9 months of age, respectively. FSGS with GBM layering were observed in both cases. They progressed to ESRD at 1 year and 6 months of age and 6 years and 6 months of age, respectively. CNI was tried in 1 case with partial proteinuria remission. Both patients were detected to have WT1 splice mutation. (3) Isolated nephropathy (IN) was observed in 8 cases: three had splice mutation, 5 had missense mutation. Of the 3 patients with splice mutation, one was found to have nephropathy and renal failure at the age of 5 months. The other two cases (1 was FSGS and another MCD), both had GBM layering. CNIs were tried on both of them, one got partial remission with normal renal function at the age of fourteen years, the other one had no response and entered ESRD at the age of 6 years and 9 months. Of the 5 cases with missense mutation, 3 had DMS, 2 of them entered ESRD within 6 months of age, another case had DMS entered ESRD at 9 years of age. One case with FSGS, was treated with CNIs and got complete remission. Conclusions: Slow progression (7/10) nephropathy was observed in DDS patients. Missense mutation (11/20) was the most common type of WT1 variants, followed by splice mutation (5/20) in this group of patients. Early onset nephropathy (4/5), rapid progression (4/5) and GBM layering (4/4) wereobserved in patients with splice mutation. CNI was effective in reducing or even eliminating proteinuria in WT1 MAN patients (8/9).