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Clinical Kidney Journal Dec 2019Denys-Drash syndrome (DDS) is a rare disease caused by mutations in exons 8 and 9 of the gene. It is characterized by the association of early onset steroid-resistant...
BACKGROUND
Denys-Drash syndrome (DDS) is a rare disease caused by mutations in exons 8 and 9 of the gene. It is characterized by the association of early onset steroid-resistant nephrotic syndrome (SRNS), Wilms' tumour and, in some patients, intersex disorders, with increasing risk of gonadoblastoma. There are few published data concerning the long-term outcome of patients with DDS. The aim of this study was to report our experience.
METHODS
Data were collected from five children (three boys) with confirmed DDS diagnosed from 1996 to 2017. The mean follow-up of these patients was 16 years.
RESULTS
The patients presented with SRNS and diffuse mesangial sclerosis at renal biopsy. All patients were hypertensive and progressed to end-stage kidney disease, initiating dialysis at a mean age of 28 months. Three patients developed Wilms' tumour 9 months after the SRNS was identified, which was treated by nephrectomy and chemotherapy. All five patients received kidney transplantation. SRNS did not recur after transplantation in any of the patients and graft survival was similar to that of other kidney transplant recipients in our programme. All three boys had ambiguous genitalia and cryptorchidism but a confirmed male karyotype (46, XY). One girl presented with gonadal agenesis, whereas the other one had normal female ovarian tissue and external genitalia. Both girls had a female karyotype (46, XX). Gonadoblastoma was not observed at any case.
CONCLUSIONS
Early DDS recognition in patients with SRNS is crucial due to its low prevalence, the specific treatment approach required and early detection of Wilms' tumour. Few data are available regarding long-term outcomes.
PubMed: 31807296
DOI: 10.1093/ckj/sfz022 -
Clinical Nephrology. Case Studies 2018Denys-Drash syndrome (DDS), a condition caused by mutations in the tumor-suppressor gene WT-1, is associated with a triad of disorders: ambiguous genitalia, nephrotic...
Denys-Drash syndrome (DDS), a condition caused by mutations in the tumor-suppressor gene WT-1, is associated with a triad of disorders: ambiguous genitalia, nephrotic syndrome leading to end-stage renal disease (ESRD), and Wilms' tumor. Given the variable disease course, management is challenging. We aimed to describe the evolution of DDS and the range of management strategies by summarizing the clinical courses of cases collected from a questionnaire sent to the international pediatric nephrology community. 15 respondents provided information on 23 patients; 21 DDS cases were confirmed and analyzed. At DDS diagnosis, 6 patients had a Wilms' tumor (group A) and 15 had no Wilms' tumor (group B). Three group A patients had unilateral nephrectomy. Two of these still had renal function, with no second tumor, at 36 months and 16 years of age, and 1 progressed to ESRD. Three had bilateral nephrectomy before ESRD. Eight group B patients progressed to ESRD, all of whom later had all renal tissue removed. Two group B patients subsequently developed a unilateral Wilms' tumor and had bilateral nephrectomy pre-ESRD. Three had bilateral nephrectomy prior to reaching ESRD without ever having a Wilms' tumor. Two group B patients remained tumor-free with renal function at last follow-up. Two main management approaches were taken: pre-emptive nephrectomy prior to ESRD and conservative surveillance. Based on the known risks associated with ESRD in infants and young children, the variable course of DDS, and the relatively good prognosis associated with Wilms' tumor, a guiding principle of preservation of renal function is most logical. Most would advocate bilateral prophylactic nephrectomy after ESRD is reached due to the high tumor risk, which is likely heightened after transplant.
PubMed: 30450273
DOI: 10.5414/CNCS109515 -
Journal of Clinical Laboratory Analysis May 2021Denys-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...
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.
Topics: Amino Acid Sequence; Asian People; Base Sequence; Cell Line, Tumor; China; Computer Simulation; Denys-Drash Syndrome; Female; Follow-Up Studies; Humans; Infant; Laparoscopy; Mutation; Pedigree; Tomography, X-Ray Computed; WT1 Proteins; Wilms Tumor
PubMed: 33942367
DOI: 10.1002/jcla.23769 -
BMC Nephrology Jul 2017Hemolytic uremic syndrome (HUS) can occur as a primary process due to mutations in complement genes or secondary to another underlying disease. HUS sometimes occurs in...
BACKGROUND
Hemolytic uremic syndrome (HUS) can occur as a primary process due to mutations in complement genes or secondary to another underlying disease. HUS sometimes occurs in the setting of glomerular diseases, and it has been described in association with Denys-Drash syndrome (DDS), which is characterized by the triad of abnormal genitourinary development; a pathognomonic glomerulopathy, diffuse mesangial sclerosis; and the development of Wilms tumor.
CASE PRESENTATION
We report the case of a 46, XX female infant who presented with HUS and biopsy-proven thrombotic microangiopathy. Next generation sequencing of genes with known mutations causative of atypical HUS found that she was homozygous for the Complement Factor H H3 haplotype and heterozygous for a variant of unknown significance in the DGKE gene. Whole exome sequencing identified a de novo heterozygous WT1 c.1384C > T; p.R394W mutation, which is classically associated with Denys-Drash syndrome (DDS). At the time of bilateral nephrectomy five months after her initial biopsy, she had diffuse mesangial sclerosis, typical of Denys-Drash syndrome, without evidence of thrombotic microangiopathy.
CONCLUSION
This unique case highlights HUS as a rare but important manifestation of WT1 mutation and provides new insight into the genetics underlying this association.
Topics: Denys-Drash Syndrome; Diagnosis, Differential; Female; Hemolytic-Uremic Syndrome; Humans; Infant; Mutation; WT1 Proteins
PubMed: 28720077
DOI: 10.1186/s12882-017-0643-1 -
Archives of Disease in Childhood Oct 1999
Review
Topics: Female; Gene Deletion; Genes, Wilms Tumor; Gonadal Dysgenesis; Humans; Kidney Diseases; Male; Mutation; Syndrome
PubMed: 10490448
DOI: 10.1136/adc.81.4.365 -
Molecular and Cellular Biology Nov 2004Renal failure is a frequent and costly complication of many chronic diseases, including diabetes and hypertension. One common feature of renal failure is...
Renal failure is a frequent and costly complication of many chronic diseases, including diabetes and hypertension. One common feature of renal failure is glomerulosclerosis, the pathobiology of which is unclear. To help elucidate this, we generated a mouse strain carrying the missense mutation Wt1 R394W, which predisposes humans to glomerulosclerosis and early-onset renal failure (Denys-Drash syndrome [DDS]). Kidney development was normal in Wt1(+/R394W) heterozygotes. However, by 4 months of age 100% of male heterozygotes displayed proteinuria and glomerulosclerosis characteristic of DDS patients. This phenotype was observed in an MF1 background but not in a mixed B6/129 background, suggestive of the action of a strain-specific modifying gene(s). WT1 encodes a nuclear transcription factor, and the R394W mutation is known to impair this function. Therefore, to investigate the mechanism of Wt1 R394W-induced renal failure, the expression of genes whose deletion leads to glomerulosclerosis (NPHS1, NPHS2, and CD2AP) was quantitated. In mutant kidneys, NPHS1 and NPHS2 were only moderately downregulated (25 to 30%) at birth but not at 2 or 4 months. Expression of CD2AP was not changed at birth but was significantly upregulated at 2 and 4 months. Podocalyxin was downregulated by 20% in newborn kidneys but not in kidneys at later ages. Two other genes implicated in glomerulosclerosis, TGFB1 and IGF1, were upregulated at 2 months and at 2 and 4 months, respectively. It is not clear whether the significant alterations in gene expression are a cause or a consequence of the disease process. However, the data do suggest that Wt1 R394W-induced glomerulosclerosis may be independent of downregulation of the genes for NPHS1, NPHS2, CD2AP, and podocalyxin and may involve other genes yet to be implicated in renal failure. The Wt1(R394W) mouse recapitulates the pathology and disease progression observed in patients carrying the same mutation, and the mutation is completely penetrant in male animals. Thus, it will be a powerful and biologically relevant model for investigating the pathobiology of the earliest events in glomerulosclerosis.
Topics: Adaptor Proteins, Signal Transducing; Animals; Base Sequence; Cell Division; Cytoskeletal Proteins; DNA; Denys-Drash Syndrome; Disease Models, Animal; Female; Gene Expression; Genes, Wilms Tumor; Glomerulosclerosis, Focal Segmental; Humans; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Electron; Phenotype; Point Mutation; Proteins; Renal Insufficiency; Species Specificity
PubMed: 15509792
DOI: 10.1128/MCB.24.22.9899-9910.2004 -
Medicine Mar 1996The chromosome-16 and the X-chromosome forms of alpha-thalassemia--ATR-16 and ATR-X--exemplify 2 important causes of syndromal mental retardation. ATR-16 is a contiguous... (Review)
Review
The chromosome-16 and the X-chromosome forms of alpha-thalassemia--ATR-16 and ATR-X--exemplify 2 important causes of syndromal mental retardation. ATR-16 is a contiguous gene syndrome which arises from loss of DNA from the tip of chromosome 16p13.3 by truncation, interstitial deletion, or unbalanced translocation. It provided the first example of a chromosome translocation that could be detected by molecular analysis but not conventional cytogenetics. It also provided the first example of a telomeric truncation giving rise to a complex genetic syndrome. In contrast ATR-X appears to be due to mutations in a trans-acting factor that regulates gene expression. Mutations in transcription factors have recently been identified in a number of genetic diseases (for example, Denys-Drash syndrome, WT1 [19]; pituitary dwarfism, PIT1 [16]; Rubinstein-Taybi syndrome, CBP [20]. Not only is this mechanism proving to be an important cause of complex syndromes but it is providing new perspectives on certain developmental pathways. XH2 may not be a classical transcription factor but it is certainly involved in the regulation of gene expression, exerting its effects on several different genes. It seems likely that other mutations in this class of regulatory proteins will be found in patients with complex disorders including mental retardation. In broader terms the 2 mechanisms described here may prove to be responsible for a significant proportion of mental retardation. However, without a feature such as alpha-thalassemia to pinpoint the area of genome or pathways involved it may prove difficult to identify other, similarly affected genes underlying other forms of mental retardation. As the human genome project and rapid genome analysis evolve this problem should become less of an obstacle. In the meantime, it is very worthwhile to continue looking for unusual clinical associations that may point to critical genes underlying human genetic disorders.
Topics: Chromosome Aberrations; Chromosome Disorders; Chromosome Mapping; Chromosomes, Human, Pair 16; Gene Deletion; Humans; Intellectual Disability; Mutation; Pedigree; Sex Chromosome Aberrations; Syndrome; Transcription, Genetic; Translocation, Genetic; X Chromosome; alpha-Thalassemia
PubMed: 8606626
DOI: 10.1097/00005792-199603000-00001 -
Annals of Medicine and Surgery (2012) Apr 2021Wilms' tumor (WT) is the most frequently occurring paediatric renal tumor and is one of the most treatment-responsive tumors. A tumor-suppressor gene and other genetic... (Review)
Review
BACKGROUND
Wilms' tumor (WT) is the most frequently occurring paediatric renal tumor and is one of the most treatment-responsive tumors. A tumor-suppressor gene and other genetic abnormalities have been implicated in its etiology. In addition, patients with many congenital anomalies, such as Beckwith-Wiedemann syndrome, WAGR syndrome and Denys-Drash syndrome, have an increased risk of WT.
METHODS AND RESULTS
Two large collaborative groups - National Wilms Tumor Study Group (NWTSG)/Children's Oncology Group (COG) and The International Society of Paediatric Oncology (SIOP) have laid down the guidelines for standardized treatment of WT, though differing in the diagnostic and therapeutic approach. The major difference in the two guidelines is the timing of surgery: SIOP recommends using preoperative chemotherapy and NWTSG/COG prefers primary surgery before any adjuvant treatments. Both these groups currently aim at intensifying treatment for patients with poor prognosticators while appropriating the therapy to reduce long-term complications for those with favourable prognostic features. As the survival rate has now reached 90%, the primary objectives of the physician are to perform nephron-sparing surgery in selected cases and to reduce the dosage and duration of chemotherapy and radiotherapy in appropriate cases. The purpose of this review is to present current standards of diagnosis and treatment of WT around the world.
CONCLUSION
Further studies in future should be done to highlight the use of chemotherapy and radiotherapy under risk-stratified strategies. Further improvement in survival of these children can only be achieved by increasing awareness, early recognition, appropriate referral, and a multidisciplinary approach.
PubMed: 33747498
DOI: 10.1016/j.amsu.2021.102202 -
Pediatric Nephrology (Berlin, Germany) Oct 2022Intronic WT1 mutations are usually causative of Frasier syndrome with focal segmental glomerulosclerosis as the characteristic nephropathy. Membranoproliferative... (Review)
Review
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.
Topics: Denys-Drash Syndrome; Frasier Syndrome; Genes, Wilms Tumor; Glomerulonephritis, Membranoproliferative; Gonadal Dysgenesis; Humans; Kidney Neoplasms; Mutation; WT1 Proteins; Wilms Tumor
PubMed: 35211794
DOI: 10.1007/s00467-022-05421-8 -
Cell Adhesion & Migration 2012Anti-angiogenic vascular endothelial growth factor A (VEGF) 165b and pro-angiogenic VEGF 165 are generated from the same transcript, and their relative amounts are... (Review)
Review
Anti-angiogenic vascular endothelial growth factor A (VEGF) 165b and pro-angiogenic VEGF 165 are generated from the same transcript, and their relative amounts are dependent on alternative splicing. The role of VEGF 165b has not been investigated in as much detail as VEGF 165, although it appears to be highly expressed in non-angiogenic tissues and, in contrast with VEGF 165, is downregulated in tumors and other pathologies associated with abnormal neovascularization such as diabetic retinopathy or Denys Drash syndrome. VEGF 165b inhibits VEGFR2 signaling by inducing differential phosphorylation, and it can be used to block angiogenesis in in vivo models of tumorigenesis and angiogenesis-related eye disease. Recent reports have identified three serine/arginine-rich proteins, SRSF1, SRSF2 and SRSF6, and studied their role in regulating terminal splice-site selection. Since the balance of VEGF isoforms is lost in cancer and angiogenesis-related conditions, control of VEGF splicing could also be used as a basis for therapy in these diseases.
Topics: Alternative Splicing; Animals; Capillary Permeability; Denys-Drash Syndrome; Diabetic Retinopathy; Glomerulonephritis; Humans; Neoplasms; Neovascularization, Pathologic; Nuclear Proteins; Phosphorylation; Protein Isoforms; RNA-Binding Proteins; Serine-Arginine Splicing Factors; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 23076130
DOI: 10.4161/cam.22439