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Medicina (Kaunas, Lithuania) 2005Constitutional missense mutations in the WT1 gene are usually associated with Denys-Drash syndrome. This rare syndrome is characterized by a rapid progressive...
Constitutional missense mutations in the WT1 gene are usually associated with Denys-Drash syndrome. This rare syndrome is characterized by a rapid progressive nephropathy, male pseudohermaphroditism, and an increased risk for Wilms tumor. We report on a patient with incomplete Denys-Drash syndrome, which was evident by the clinical data and proved by molecular genetics methods. The patient has the mutation p.R394W in the WT1 gene and clinical symptoms of Denys-Drash syndrome.
Topics: Denys-Drash Syndrome; Exons; Female; Genes, Wilms Tumor; Humans; Infant; Mutation, Missense; WT1 Proteins
PubMed: 15758579
DOI: No ID Found -
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 -
Nucleic Acids Research Dec 2016Mutations in human zinc-finger transcription factor WT1 result in abnormal development of the kidneys and genitalia and an array of pediatric problems including...
Mutations in human zinc-finger transcription factor WT1 result in abnormal development of the kidneys and genitalia and an array of pediatric problems including nephropathy, blastoma, gonadal dysgenesis and genital discordance. Several overlapping phenotypes are associated with WT1 mutations, including Wilms tumors, Denys-Drash syndrome (DDS), Frasier syndrome (FS) and WAGR syndrome (Wilms tumor, aniridia, genitourinary malformations, and mental retardation). These conditions vary in severity from individual to individual; they can be fatal in early childhood, or relatively benign into adulthood. DDS mutations cluster predominantly in zinc fingers (ZF) 2 and 3 at the C-terminus of WT1, which together with ZF4 determine the sequence-specificity of DNA binding. We examined three DDS associated mutations in ZF2 of human WT1 where the normal glutamine at position 369 is replaced by arginine (Q369R), lysine (Q369K) or histidine (Q369H). These mutations alter the sequence-specificity of ZF2, we find, changing its affinity for certain bases and certain epigenetic forms of cytosine. X-ray crystallography of the DNA binding domains of normal WT1, Q369R and Q369H in complex with preferred sequences revealed the molecular interactions responsible for these affinity changes. DDS is inherited in an autosomal dominant fashion, implying a gain of function by mutant WT1 proteins. This gain, we speculate, might derive from the ability of the mutant proteins to sequester WT1 into unproductive oligomers, or to erroneously bind to variant target sequences.
Topics: Adenine; Amino Acid Substitution; Crystallography, X-Ray; Cytosine; DNA; Denys-Drash Syndrome; Epigenesis, Genetic; Glutamine; Guanine; Humans; Mutation; WT1 Proteins
PubMed: 27596598
DOI: 10.1093/nar/gkw766 -
Annals of Pediatric Endocrinology &... Jun 2014There is a wide variety of genital abnormalities observed in patients with Denys-Drash syndrome (DDS). WT1 is thought to influence the genes related to genital...
There is a wide variety of genital abnormalities observed in patients with Denys-Drash syndrome (DDS). WT1 is thought to influence the genes related to genital development and mutations in this gene have been associated with DDS. DDS should be considered in the differential diagnosis of newborns with genital anomalies. In contrast to other conditions with 46,XY disorders of sex development, individuals with DDS often have duplicated genital organs (a double vagina, cervix or uterus). A double uterus has not yet been reported with 1390G>A (Arg464 Asn) mutation. However, duplicated genitals have been reported with other genetic mutations in patients with DDS. The duplicated genitals in DDS may be associated with low anti-Mullerian hormone (AMH) secretion. Measurement of the AMH levels may add to our understanding of variations in genital development and their abnormalities in disorders such as DDS. In conclusion, this is first case of low level of AMH and double uterus in 1390G>A (Arg464 Asn) mutations of DDS male.
PubMed: 25077094
DOI: 10.6065/apem.2014.19.2.100 -
Journal of Medical Genetics Jun 1994
Review
Topics: Abnormalities, Multiple; Diagnosis, Differential; Disorders of Sex Development; Female; Genes, Wilms Tumor; Humans; Male; Mosaicism; Nephrosclerosis; Point Mutation; Syndrome; Wilms Tumor
PubMed: 8071974
DOI: 10.1136/jmg.31.6.471 -
The American Journal of Pathology Jan 1999Denys-Drash syndrome is a rare disorder of urogenital development characterized by the association of early onset glomerulopathy caused by diffuse mesangial sclerosis,...
Denys-Drash syndrome is a rare disorder of urogenital development characterized by the association of early onset glomerulopathy caused by diffuse mesangial sclerosis, gonadal dysgenesis leading to pseudohermaphroditism in males, and a high risk of developing Wilms' tumor. The syndrome is caused by dominant negative point mutations in the WT1 gene that encodes a tumor suppressor transcription factor normally expressed in podocytes. Mutations usually affect the zinc fingers of the WT1 protein. The basic defect is unknown in most cases of isolated diffuse mesangial sclerosis, a disease characterized by the same glomerular changes as in Denys-Drash syndrome but possibly transmitted as an autosomal recessive trait. Here we show that the distribution of WT1 is abnormal in most patients with Denys-Drash syndrome : WT1 nuclear staining of podocytes is decreased or absent. This finding is consistent with the decreased DNA binding capacity of the mutated protein. One target gene of WT1 is PAX2, the expression of which is down-regulated in podocytes during early stages of nephrogenesis. We demonstrate that WT1 mislocalization is associated with abnormal podocyte expression of PAX2 protein and RNA. We suggest that persistent expression of PAX2 is likely to result from the loss of WT1 dependent transcriptional repression and may participate in the pathological mechanisms leading to glomerular dysfunction. Abnormal distribution of WT1 and PAX2 was also observed in isolated diffuse mesangial sclerosis suggesting that a defect in WT1 could also be operative in isolated diffuse mesangial sclerosis. Primary involvement of PAX2 is an alternative hypothesis because persistent expression of PAX2 in transgenic mice is associated with the occurrence of early and severe glomerulopathy.
Topics: Animals; DNA-Binding Proteins; Developmental Disabilities; Female; Female Urogenital Diseases; Fetus; Genitalia; Glomerular Mesangium; Glomerulosclerosis, Focal Segmental; Humans; Infant, Newborn; Kidney Diseases; Kidney Glomerulus; Male; Male Urogenital Diseases; PAX2 Transcription Factor; Sclerosis; Syndrome; Transcription Factors; WT1 Proteins
PubMed: 9916932
DOI: 10.1016/S0002-9440(10)65264-9 -
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