-
The Tohoku Journal of Experimental... Sep 2020Denys-Drash syndrome is characterized by progressive nephropathy, gonadal dysgenesis, and Wilms tumor caused by a WT1 gene mutation. Infants with Denys-Drash syndrome...
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.
Topics: Age of Onset; Denys-Drash Syndrome; Humans; Hypertension; Hypotension; Infant; Infant, Newborn; Nephrectomy; Organ Specificity
PubMed: 32863338
DOI: 10.1620/tjem.252.45 -
Journal of Clinical Research in... Aug 2021We 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...
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.
Topics: Adolescent; Biotin; Castration; Denys-Drash Syndrome; Diagnostic Errors; Dietary Supplements; Female; Humans; Hyperandrogenism; Immunoassay; Kidney Failure, Chronic; Predictive Value of Tests; Testosterone
PubMed: 32840097
DOI: 10.4274/jcrpe.galenos.2020.2020.0064 -
Frontiers in Pediatrics 2020The variant is confirmed to be pathogenic for Denys-Drash syndrome (DDS), a rare disorder characterized by early-onset nephrotic syndrome and renal failure,...
The variant is confirmed to be pathogenic for Denys-Drash syndrome (DDS), a rare disorder characterized by early-onset nephrotic syndrome and renal failure, pseudo-hermaphroditism, and a high risk of Wilms' tumor. Several cases of DDS presenting with atypical hemolytic uremic syndrome (aHUS) have been reported. Here we report the case of a 2-year-old child who was diagnosed with missense variant, associated with DDS and initial presentation of aHUS. Complement factor H autoantibodies were negative. Complement regulatory system-related gene variants were not found, but a heterozygous c.754G>A missense variant in exon 9 of gene was detected, resulting in a p. Asp252Asn substitution, by next-generation sequencing. The patient was a female morphologically but proved to be a genetic male because of karyotype 46, XY with normally developed female external genitalia. Bilateral nephrectomy and renal transplantation were performed 1 year later, and there was no recurrence of aHUS at 10 months after transplantation.
PubMed: 33392118
DOI: 10.3389/fped.2020.605889 -
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 -
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 -
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 -
Translational Andrology and Urology Oct 2020Predisposing syndromes associated with an increased risk of Wilms tumor (WT) are responsible for 9-17% of all cases of the malignancy. Due to an earlier age at WT... (Review)
Review
Predisposing syndromes associated with an increased risk of Wilms tumor (WT) are responsible for 9-17% of all cases of the malignancy. Due to an earlier age at WT diagnosis and an increased incidence of bilateral and metachronous disease, management of syndromic WT warrants a distinct approach from that of non-syndromic WT. This review of English-language manuscripts about WT focuses on the most common syndromes, surveillance protocols and current treatment strategies. Highlighted syndromes include those associated with , such as WAGR (Wilms-Aniridia-Genitourinary-mental Retardation), Denys-Drash syndrome (DDS), and Frasier syndrome, defects, such as Beckwith-Wiedemann syndrome (BWS), among others. General surveillance guidelines include screening renal or abdominal ultrasound every 3-4 months until the age of 5 or 7, depending on the syndrome. Further, some of the predisposing conditions also increase the risk of other malignancies, such as gonadoblastoma and hepatoblastoma. With promising results for nephron-sparing surgery in bilateral non-syndromic WT, there are increasing reports and recommendations to pursue nephron-sparing for these patients who are at greater risk of bilateral, metachronous lesions. In addition to the loss of renal parenchyma from malignancy, many patients are at risk of developing renal insufficiency as part of their syndrome. Although there may be some increase in the complication rate, recurrence free survival seems equivalent. Some conditions require specialized approaches to adjuvant therapy, as their syndrome may make them especially susceptible to side effects.
PubMed: 33209710
DOI: 10.21037/tau.2020.03.27 -
Frontiers in Pediatrics 2023This study aimed to analyze the clinical characteristics of nephropathy associated with gene mutations in Chinese children and explore the relationship between genotype...
INTRODUCTION
This study aimed to analyze the clinical characteristics of nephropathy associated with gene mutations in Chinese children and explore the relationship between genotype and clinical phenotype.
METHODS
Cases diagnosed at the Guangzhou Women and Children's Medical Center, were combined with those retrieved from PubMed and China National Knowledge Infrastructure (CNKI) databases from January 2015 to June 2022 and integrated into a study cohort; grouped according to gene mutation sites, clinical phenotype, and renal pathological types. The clinical characteristics between groups were compared, and the relationship between genotype and age of onset, clinical phenotype, and pathological type were retrospectively analyzed.
RESULTS
The center enrolled 15 confirmed children: seven cases of non-simple nephropathy, including Denys-Drash syndrome (DDS) and Frasier syndrome (FS); eight cases of isolated steroid-resistant nephrotic syndrome (ISRNS); and 13 cases (86.7%) that progressed to end-stage renal disease (ESRD). The initial hemoglobin and bicarbonate levels of patients with clinical non-simple nephropathy were significantly lower than those with simple nephropathy, whereas the serum creatinine levels were higher than those of patients with simple nephropathy. A total of 75 cases of nephropathy associated with mutations in the study cohort met the inclusion and exclusion criteria. The most common clinical manifestations of mutations in this cohort were DDS (29/75, 38.7%) and ISRNS (37/75, 49.3%). A renal biopsy was performed in 43 patients, and the common types of renal pathology were focal segmental glomerulosclerosis (23/43, 53.5%) and DMS (13/43, 30.2%). Within the cohort, there were 12 cases (16.0%) in the exon 8 mutation group, 32 (42.6%) in the exon 9 group, 19 (25.3%) in the intron 9 group, and 12 (16.0%) in other gene site mutation groups. Common sites of mutations in Chinese children were exons 9 and intron 9. Exon 8 mutations were uniquely correlated with the age of onset within three months [5/7; 71.4%; Adjusted standardized residual (AR) = 4.2]. The renal survival time in the exon 8 mutation group was the shortest ( = 0.003).
DISCUSSION
The molecular and biological characteristics of mutation-related nephropathy determine the clinical type, pathological features, and renal survival time of the disease; and there was a strong correlation between the genotype and clinical phenotype.
PubMed: 37576146
DOI: 10.3389/fped.2023.1192021